Pyrrolidine derivative hair growth compositions and uses

ABSTRACT

This invention relates to pharmaceutical compositions and methods for treating alopecia and promoting hair growth using pyrrolidine derivatives.

[0001] This application is a continuation-in-part of U.S. patentapplication Ser. No. 09/089,416, filed on Jun. 3, 1998, which is acontinuation-in-part of U.S. patent application Ser. No. 08/869,426,filed on Jun. 4, 1997, now U.S. Pat. No. 5,945,441, the entire contentsof which are herein incorporated by reference.

BACKGROUND OF THE INVENTION

[0002] 1. Field of Invention

[0003] This invention relates to pharmaceutical compositions methods fortreating alopecia and promoting hair growth using pyrrolidinederivatives.

[0004] 2. Description of Related Art

[0005] Hair loss occurs in a variety of situations. These situationsinclude male pattern alopecia, alopecia senilis, alopecia areata,diseases accompanied by basic skin lesions or tumors, and systematicdisorders such as nutritional disorders and internal secretiondisorders. The mechanisms causing hair loss are very complicated, but insome instances can be attributed to aging, genetic disposition, theactivation of male hormones, the loss of blood supply to hair follicles,and scalp abnormalities.

[0006] The immunosuppressant drugs FK506, rapamycin and cyclosporin arewell known as potent T-cell specific immunosuppressants, and areeffective against graft rejection after organ transplantation. It hasbeen reported that topical, but not oral, application of FK506 (Yamamotoet al., J. Invest. Dermatol., 1994, 102, 160-164; Jiang et al., J.Invest. Dermatol. 1995, 104, 523-525) and cyclosporin (Iwabuchi et al.,J. Dermatol. Sci. 1995, 9, 64-69) stimulates hair growth in adose-dependent manner. One form of hair loss, alopecia areata, is knownto be associated with autoimmune activities; hence, topicallyadministered immunomodulatory compounds are expected to demonstrateefficacy for treating that type of hair loss. The hair growthstimulating effects of FK506 have been the subject of an internationalpatent filing covering FK506 and structures related thereto for hairgrowth stimulation (Honbo et al., EP 0 423 714 A2). Honbo et al.discloses the use of relatively large tricyclic compounds, known fortheir immunosuppressive effects, as hair revitalizing agents.

[0007] The hair growth and revitalization effects of FK506 and relatedagents are disclosed in many U.S. patents (Goulet et al., U.S. Pat. No.5,258,389; Luly et al., U.S. Pat. No. 5,457,111; Goulet et al., U.S.Pat. No. 5,532,248; Goulet et al., U.S. Pat. No. 5,189,042; and Ok etal., U.S. Pat. No. 5,208,241; Rupprecht et al., U.S. Pat. No. 5,284,840;Organ et al., U.S. Pat. No. 5,284,877). These patents claim FK506related compounds. Although they do not claim methods of hairrevitalization, they disclose the known use of FK506 for effecting hairgrowth. Similar to FK506 (and the claimed variations in the Honbo et al.patent), the compounds claimed in these patents are relatively large.Further, the cited patents relate to immunomodulatory compounds for usein autoimmune related diseases, for which FK506's efficacy is wellknown.

[0008] Other U.S. patents disclose the use of cyclosporin and relatedcompounds for hair revitalization (Hauer et al., U.S. Pat. No.5,342,625; Eberle, U.S. Pat. No. 5,284,826; Hewitt et al., U.S. Pat. No.4,996,193). These patents also relate to compounds useful for treatingautoimmune diseases and cite the known use of cyclosporin and relatedimmunosuppressive compounds for hair growth.

[0009] However, immunosuppressive compounds by definition suppress theimmune system and also exhibit other toxic side effects. Accordingly,there is a need for non-immunosuppressant, small molecule compoundswhich are useful as hair revitalizing compounds.

[0010] Hamilton and Steiner disclose in U.S. Pat. No. 5,614,547 novelpyrrolidine carboxylate compounds which bind to the immunophilin FKBP12and stimulate nerve growth, but which lack immunosuppressive effects.Unexpectedly, it has been discovered that these non-immunosuppressantcompounds promote hair growth with an efficacy similar to FK506. Yettheir novel small molecule structure and non-immunosuppressiveproperties differentiate them from FK506 and related immunosuppressivecompounds found in the prior art.

SUMMARY OF THE INVENTION

[0011] The present invention relates to a method for treating alopeciaor promoting hair growth in an animal in need thereof, which comprisesadministering to said animal an effective amount of a pyrrolidinederivative.

[0012] The present invention further relates to a pharmaceuticalcomposition which comprises:

[0013] (i) an effective amount of a pyrrolidine derivative for treatingalopecia or promoting hair growth in an animal in need thereof; and

[0014] (ii) a pharmaceutically acceptable carrier.

[0015] The pyrrolidine derivative used in the inventive method andpharmaceutical composition preferably has an affinity for FKBP-typeimmunophilins and does not exert any significant immunosuppressiveactivity.

BRIEF DESCRIPTION OF THE DRAWINGS

[0016]FIG. 1 is a photograph of C57 Black 6 mice before being shaved forthe experiment. FIG. 1 shows the condition of the mice prior to theexperiment.

[0017]FIG. 2 is a photograph of mice treated with a vehicle after sixweeks. FIG. 2 shows that less than 3% of the shaved area is covered withnew hair growth when the vehicle (control) is administered.

[0018]FIG. 3 is a photograph of mice treated with 10 μM of GPI 1046after six weeks. FIG. 3 shows the remarkable effects of pyrrolidinederivatives wherein 90% of the shaved area is covered with new hairgrowth.

[0019]FIG. 4 is a photograph of mice treated with 30 μM of GPI 1046after six weeks. FIG. 4 shows the remarkable ability of pyrrolidinederivatives to achieve, essentially, complete hair regrowth in theshaved area.

[0020]FIG. 5 is a bar graph depicting the relative hair growth indicesof mice treated with a vehicle, FK506, pyrrolidine derivatives of thepresent invention, and various related compounds 14 days after treatmentwith each identified compound. FIG. 5 demonstrates the remarkable earlyhair growth promoted by pyrrolidine derivatives and other relatedcompounds.

DETAILED DESCRIPTION OF THE INVENTION Definitions

[0021] “Alopecia” refers to deficient hair growth and partial orcomplete loss of hair, including without limitation androgenic alopecia(male pattern baldness), toxic alopecia, alopecia senilis, alopeciaareata, alopecia pelada and trichotillomania. Alopecia results when thepilar cycle is disturbed. The most frequent phenomenon is a shorteningof the hair growth or anagen phase due to cessation of cellproliferation. This results in an early onset of the catagen phase, andconsequently a large number of hairs in the telogen phase during whichthe follicles are detached from the dermal papillae, and the hairs fallout. Alopecia has a number of etiologies, including genetic factors,aging, local and systemic diseases, febrile conditions, mental stresses,hormonal problems, and secondary effects of drugs.

[0022] “GPI 1605” refers to a compound of formula

[0023] “GPI 1046” refers to 3-(3-pyridyl)-1-propyl(2s)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate, acompound of formula

[0024] “GPI 1312” refers to a compound of formula

[0025] “GPI 1572” refers to a compound of formula

[0026] “GPI 1389” refers to a compound of formula

[0027] “GPI 1511” refers to a compound of formula

[0028] “GPI 1234” refers to a compound of formula

[0029] “Isomers” refer to different compounds that have the samemolecular formula. “Stereoisomers” are isomers that differ only in theway the atoms are arranged in space. “Enantiomers” are a pair ofstereolsomers that are non-superimposable mirror images of each other.“Diastereoisomers” are stereoisomers which are not mirror images of eachother. “Racemic mixture” means a mixture containing equal parts ofindividual enantiomers. “Non-racemic mixture” is a mixture containingunequal parts of individual enantiomers or stereoisomers.

[0030] “Pharmaceutically acceptable salt” refers to a salt of theinventive compounds which possesses the desired pharmacological activityand which is neither biologically nor otherwise undesirable. The saltcan be formed with inorganic acids such as acetate, adipate, alginate,aspartate, benzoate, benzenesulfonate, bisulfate butyrate, citrate,camphorate, camphorsulfonate, cyclopentanepropionate, digluconate,dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate,glycerophosphate, hemisulfate heptanoate, hexanoate, hydrochloridehydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,methanesuifonate, 2-naphthalenesulfonate, nicotinate, oxalate,thiocyanate, tosylate and undecanoate. Examples of a base salt includeammonium salts, alkali metal salts such as sodium and potassium salts,alkaline earth metal salts such as calcium and magnesium salts, saltswith organic bases such as dicyclohexylamine salts,N-methyl-D-glucamine, and salts with amino acids such as arginine andlysine. Also, the basic nitrogen-containing groups can be quarternizedwith agents including: lower alkyl halides such as methyl, ethyl,propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates suchas dimethyl, diethyl, dibutyl and diamyl sulfates; long chain halidessuch as decyl, lauryl, myristyl and stearyl chlorides, bromides andiodides; and aralkyl halides such as benzyl and phenethyl bromides.

[0031] “Pilar cycle” refers to the life cycle of hair follicles, andincludes three phases:

[0032] (1) the anagen phase, the period of active hair growth which,insofar as scalp hair is concerned, lasts about three to five years;

[0033] (2) the catagen phase, the period when growth stops and thefollicle atrophies which, insofar as scalp hair is concerned, lastsabout one to two weeks; and

[0034] (3) the telogen phase, the rest period when hair progressivelyseparates and finally falls out which, insofar as scalp hair isconcerned, lasts about three to four months.

[0035] Normally 80 to 90 percent of the follicles are in the anagenphase, less than 1 percent being in the catagen phase, and the restbeing in the telogen phase. In the telogen phase, hair is uniform indiameter with a slightly bulbous, non-pigmented root. By contrast, inthe anagen phase, hair has a large colored bulb at its root.

[0036] “Promoting hair growth” refers to maintaining, inducing,stimulating, accelerating, or revitalizing the germination of hair.

[0037] “Treating alopecia” refers to:

[0038] (i) preventing alopecia in an animal which may be predisposed toalopecia; and/or

[0039] (ii) inhibiting, retarding or reducing alopecia; and/or

[0040] (iii) promoting hair growth; and/or

[0041] (iv) prolonging the anagen phase of the hair cycle; and/or

[0042] (v) converting vellus hair to growth as terminal hair. Terminalhair is coarse, pigmented, long hair in which the bulb of the hairfollicle is seated deep in the dermis. Vellus hair, on the other hand,is fine, thin, non-pigmented short hair in which the hair bulb islocated superficially in the dermis. As alopecia progresses, the hairschange from the terminal to the vellus type.

Methods of the Present Invention

[0043] The present invention relates to a method for treating alopeciaor promoting hair growth in an animal, which comprises administering tosaid animal an effective amount of a pyrrolidine derivative.

[0044] The inventive method is particularly useful for treating malepattern alopecia, alopecia senilis, alopecia areata, alopecia resultingfrom skin lesions or tumors, alopecia resulting from cancer therapy suchas chemotherapy and radiation, and alopecia resulting from systematicdisorders such as nutritional disorders and internal secretiondisorders.

Pharmaceutical Compositions of the Present Invention

[0045] The present invention also relates to a pharmaceuticalcomposition comprising:

[0046] (i) an effective amount of a pyrrolidine derivative for treatingalopecia or promoting hair growth in an animal in need thereof; and

[0047] (ii) a pharmaceutically acceptable carrier.

Pyrrolidine Derivatives

[0048] The pyrrolidine derivative used in the method and pharmaceuticalcomposition of the present invention is preferably a low molecularweight, small molecule compound having an affinity for an FKBP-typeimmunophilin, such as FKBP12. When the compound binds to an FKBP-typeimmunophilin, it has been found to inhibit the prolyl-peptidyl cis-transisomerase activity, or rotamase, activity of the binding protein.Unexpectedly, the compound has also been found to stimulate hair growth.Preferably, the compound is devoid of any significant immunosuppressiveactivity.

[0049] Examples of a pyrrolidine derivative that may be used in theinventive method and pharmaceutical composition are set forth below.

Formula I

[0050] A compound of the invention may be of formula I

[0051] or a pharmaceutically acceptable salt, ester, or solvate thereof,wherein:

[0052] R₁ is C₁-C₉ straight or branched chain alkyl, C₂-C₉ straight orbranched chain alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl or Ar₁,

[0053]  wherein said R₁ is unsubstituted or substituted with one or moresubstituents independently selected from the group consisting of C₁-C₆alkyl, C₂-C₆ alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, hydroxy, andAr₂;

[0054] Ar₁ and Ar₂ are independently selected from the group consistingof 1-naphthyl, 2-naphthyl, 2-indolyl, 3-indolyl, 2-furyl, 3-furyl,2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and phenyl,

[0055]  wherein said Ar₁ is unsubstituted or substituted with one ormore substituent(s) independently selected from the group consisting ofhydrogen, halo, hydroxy, nitro, trifluoromethyl, C₁-C₆ straight orbranched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C₁-C₄alkoxy, C₂-C₄ alkenyloxy, phenoxy, benzyloxy, and amino;

[0056] X is O, S, CH₂, or two hydrogen atoms;

[0057] Y is O or NR₂;

[0058] R₂ is hydrogen or C₁-C₆ alkyl;

[0059] Z is C₁-C₆ straight or branched chain alkyl, or C₂-C₆ straight orbranched chain alkenyl,

[0060]  wherein said Z is substituted with one or more substituent(s)independently selected from the group consisting of Ar₁, C₃-C₈cycloalkyl, C₁-C₆ straight or branched chain alkyl substituted withC₃-C₈ cycloalkyl, and C₂-C₆ straight or branched chain alkenylsubstituted with C₃-C₈ cycloalkyl,

[0061] or Z is the fragment

[0062] wherein:

[0063] R₃ is C₁-C₉ straight or branched chain alkyl which isunsubstituted or substituted with C₃-C₈ cycloalkyl or Ar₁;

[0064] X₂ is O or NR₅;

[0065] R₅ is selected from the group consisting of hydrogen, C₁-C₆straight or branched chain alkyl, and C₂-C₆ straight or branched chainalkenyl; and

[0066] R₄ is selected from the group consisting of phenyl, benzyl, C₁-C₅straight or branched chain alkyl, C₂-C₅ straight or branched chainalkenyl, C₁-C₅ straight or branched chain alkyl substituted with phenyl,and C₂-C₅ straight or branched chain alkenyl substituted with phenyl.

[0067] In a preferred embodiment of formula I, Z and R₁ are lipophilic.

[0068] In a more preferred embodiment of formula I, the compound isselected from the group consisting of:

[0069] 3-phenyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;

[0070] 3-phenyl-1-prop-2-(E)-enyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;

[0071] 3-(3,4,5-trimethoxyphenyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;

[0072] 3-(3,4,5-trimethoxyphenyl)-1-prop-2-(E)-enyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;

[0073] 3-(4,5-dichlorophenyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;

[0074] 3-(4,5-dichlorophenyl)-1-prop-2-(E)-enyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;

[0075] 3-(4,5-methylenedioxyphenyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;

[0076] 3-(4,5-methylenedioxyphenyl)-1-prop-2-(E)-enyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;

[0077] 3-cyclohexyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;

[0078] 3-cyclohexyl-1-prop-2-(E)-enyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;

[0079] (1R)-1,3-diphenyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;

[0080] (1R)-1,3-diphenyl-1-prop-2-(E)-enyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;

[0081] (1R)-1-cyclohexyl-3-phenyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;

[0082] (1R)-1-cyclohexyl-3-phenyl-1-prop-2-(E)-enyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;

[0083] (1R)-1-(4,5-dichlorophenyl)-3-phenyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;

[0084] 3-phenyl-1-propyl(2S)-1-(1,2-dioxo-2-cyclohexyl)ethyl-2-pyrrolidinecarboxylate;

[0085] 3-phenyl-1-propyl(2S)-1-(1,2-dioxo-4-cyclohexyl)butyl-2-pyrrolidinecarboxylate;

[0086] 3-phenyl-1-propyl(2S)-1-(1,2-dioxo-2-[2-furanyl])ethyl-2-pyrrolidinecarboxylate;

[0087] 3-phenyl-1-propyl(2S)-1-(1,2-dioxo-2-[2-thienyl])ethyl-2-pyrrolidinecarboxylate;

[0088] 3-phenyl-1-propyl(2S)-1-(1,2-dioxo-2-[2-thiazolyl])ethyl-2-pyrrolidinecarboxylate;

[0089] 3-phenyl-1-propyl(2S)-1-(1,2-dioxo-2-phenyl)ethyl-2-pyrrolidinecarboxylate;

[0090] 1,7-diphenyl-4-heptyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;

[0091] 3-phenyl-1-propyl (2S)1-(3,3-dimethyl-1,2-dioxo-4-hydroxybutyl)-2-pyrrolidinecarboxylate;

[0092] 3-phenyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxamide;

[0093] 1-[1-(3,3-dimethyl-1,2-dioxopentyl)-L-proline]-L-phenylalanineethyl ester;

[0094] 1-[1-(3,3-dimethyl-1,2-dioxopentyl)-L-proline]-L-leucine ethylester;

[0095] 1-[1-(3,3-dimethyl-1,2-dioxopentyl)-L-proline]-L-phenylglycineethyl ester;

[0096] 1-[1-(3,3-dimethyl-1,2-dioxopentyl)-L-proline]-L-phenylalaninephenyl ester;

[0097] 1-[1-(3,3-dimethyl-1,2-dioxopentyl)-L-proline]-L-phenylalaninebenzyl ester; and

[0098] 1-[1-(3,3-dimethyl-1,2-dioxopentyl)-L-proline]-L-isoleucine ethylester;

[0099] or a pharmaceutically acceptable salt, ester, or solvate thereof.

Formula II

[0100] Additionally, a compound of the invention may be of formula II

[0101] or a pharmaceutically acceptable salt, ester, or solvate thereof,wherein:

[0102] R₁ is C₁-C₉ straight or branched chain alkyl, C₂-C₉ straight orbranched chain alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl or Ar₁,

[0103]  wherein said R₁ is unsubstituted or substituted with one or moresubstituents independently selected from the group consisting of C₁-C₆alkyl, C₂-C₆ alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, hydroxy, andAr₂;

[0104] Ar₁ and Ar₂ are independently selected from the group consistingof 1-naphthyl, 2-naphthyl, 2-indolyl, 3-indolyl, 2-furyl, 3-furyl,2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and phenyl,

[0105]  wherein said Ar₁ is unsubstituted or substituted with one ormore substituent(s) independently selected from the group consisting ofhydrogen, halo, hydroxy, nitro, trifluoromethyl, C₁-C₆ straight orbranched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C₁-C₄alkoxy, C₂-C₄ alkenyloxy, phenoxy, benzyloxy, and amino;

[0106] Z is C₁-C₆ straight or branched chain alkyl, or C₂-C₆ straight orbranched chain alkenyl,

[0107]  wherein said Z is substituted with one or more substituent(s)independently selected from the group consisting of Ar₁, C₃-C₈cycloalkyl, C₁-C₆ straight or branched chain alkyl substituted withC₃-C₈ cycloalkyl, and C₂-C₆ straight or branched chain alkenylsubstituted with C₃-C₈ cycloalkyl, or Z is the fragment

[0108] wherein:

[0109] R₃ is C₁-C₉ straight or branched chain alkyl which isunsubstituted or substituted with C₃-C₈ cycloalkyl or Ar₁;

[0110] X₂ is O or NR₅;

[0111] R₅ is selected from the group consisting of hydrogen, C₁-C₆straight or branched chain alkyl, and C₂-C₆ straight or branched chainalkenyl; and

[0112] R₄ is selected from the group consisting of phenyl, benzyl, C₁-C₅straight or branched chain alkyl, C₂-C₅ straight or branched chainalkenyl, C₁-C₅ straight or branched chain alkyl substituted with phenyl,and C₂-C₅ straight or branched chain alkenyl substituted with phenyl.

[0113] In a preferred embodiment of formula II, R₁ is selected from thegroup consisting of C₁-C₉ straight or branched chain alkyl,2-cyclohexyl, 4-cyclohexyl, 2-furanyl, 2-thienyl, 2-thiazolyl, and4-hydroxybutyl.

[0114] In another preferred embodiment of formula II, Z and R₁ arelipophilic.

Formula III

[0115] Furthermore, a compound of the invention may be of formula III

[0116] or a pharmaceutically acceptable salt, ester, or solvate orhydrate thereof, wherein:

[0117] Z′ is the fragment

[0118] wherein:

[0119] R₃ is C₁-C₉ straight or branched chain alkyl or unsubstitutedAr₁,

[0120]  wherein said alkyl is unsubstituted or substituted with C₃-C₈cycloalkyl or Ar₁;

[0121] X₂ is O or NR₅;

[0122] R₅ is selected from the group consisting of hydrogen, C₁-C₆straight or branched chain alkyl, and C₂-C₆ straight or branched chainalkenyl;

[0123] R₄ is selected from the group consisting of phenyl, benzyl, C₁-C₅straight or branched chain alkyl, C₂-C₅ straight or branched chainalkenyl, C₁-C₅ straight or branched chain alkyl substituted with phenyl,and C₂-C₅ straight or branched chain alkenyl substituted with phenyl;and

[0124] Ar₁ is independently selected from the group consisting of1-naphthyl, 2-naphthyl, 2-indolyl, 3-indolyl, 2-furyl, 3-furyl,2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and phenyl,

[0125]  wherein said Ar₁ is unsubstituted or substituted with one ormore substituent(s) independently selected from the group consisting ofhydrogen, halo, hydroxy, nitro, trifluoromethyl, C₁-C₆ straight orbranched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C₁-C₄alkoxy, C₂-C₄ alkenyloxy, phenoxy, benzyloxy, and amino.

[0126] In a preferred embodiment of formula III, Z′ is lipophilic.

Formula IV

[0127] A compound of the invention may also be of formula IV

[0128] or a pharmaceutically acceptable salt, ester, or solvate thereof,wherein:

[0129] R₁ is C₁-C₆ straight or branched chain alkyl, C₂-C₆ straight orbranched chain alkenyl, C₃-C₆ cycloalkyl or Ar₁,

[0130]  wherein said alkyl or alkenyl is unsubstituted or substitutedwith C₃-C₆ cycloalkyl or Ar₂;

[0131] Ar₁ and Ar₂ are independently selected from the group consistingof 2-furyl, 2-thienyl, and phenyl;

[0132] X is selected from the group consisting of oxygen and sulfur;

[0133] Y is oxygen;

[0134] Z is C₁-C₆ straight or branched chain alkyl or C₂-C₆ straight orbranched chain alkenyl,

[0135]  wherein said Z is substituted with one or more substituent(s)independently selected from the group consisting of 2-furyl, 2-thienyl,C₃-C₆ cycloalkyl, pyridyl, and phenyl, each having one or moresubstituent(s) independently selected from the group consisting ofhydrogen and C₁-C₄ alkoxy.

[0136] In a preferred embodiment of formula IV, Z and R₁ are lipophilic.

[0137] In another preferred embodiment of formula IV, the compound isselected from the group consisting of:

[0138] 3-(2,5-dimethoxyphenyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;

[0139] 3-(2,5-dimethoxyphenyl)-1-prop-2-(E)-enyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;

[0140] 2-(3,4,5-trimethoxyphenyl)-1-ethyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;

[0141] 3-(3-pyridyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;

[0142] 3-(2-pyridyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;

[0143] 3-(4-pyridyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;

[0144] 3-phenyl-1-propyl(2S)-i-(2-tert-butyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate;

[0145] 3-phenyl-1-propyl(2S)-1-(2-cyclohexylethyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate;

[0146] 3-(3-pyridyl)-1-propyl(2S)-1-(2-cyclohexylethyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate;

[0147] 3-(3-pyridyl)-1-propyl(2S)-1-(2-tert-butyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate;

[0148] 3,3-diphenyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;

[0149] 3-(3-pyridyl)-1-propyl(2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate;

[0150] 3-(3-pyridyl)-1-propyl(2S)-N-([2-thienyl]glyoxyl)pyrrolidinecarboxylate;

[0151] 3,3-diphenyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxobutyl)-2-pyrrolidinecarboxylate;

[0152] 3,3-diphenyl-1-propyl(2S)-1-cyclohexylglyoxyl-2-pyrrolidinecarboxylate; and

[0153] 3,3-diphenyl-1-propyl(2S)-1-(2-thienyl)glyoxyl-2-pyrrolidinecarboxylate;

[0154] or a pharmaceutically acceptable salt, ester, or solvate thereof.

[0155] In a more preferred embodiment of formula IV, the compound isselected from the group consisting of:

[0156] 3-(3-pyridyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;

[0157] 3-(2-pyridyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate; and

[0158] 3-(3-pyridyl)-1-propyl(2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate;

[0159] or a pharmaceutically acceptable salt, ester, or solvate thereof.

[0160] In the most preferred embodiment of formula IV, the compound is3-(3-pyridyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidine-carboxylate, andpharmaceutically acceptable salts, esters, and solvates thereof.

Formula V

[0161] Additionally, a compound of the invention may be of formula V

[0162] or a pharmaceutically acceptable salt, ester, or solvate thereof,wherein:

[0163] V is CH or N;

[0164] A and B, taken together with V and the carbon atom to which theyare respectively attached, form a 5-7 membered saturated or unsaturatedheterocyclic ring containing one or more heteroatom(s) selected from thegroup consisting of O, S, SO, SO₂, N, NH, and NR;

[0165] R is C₁-C₉ straight or branched chain alkyl, C₂-C₉ straight orbranched chain alkenyl, C₃-C₉ cycloalkyl, C₁-C₇ cycloalkenyl, or Ar₁,

[0166]  wherein said R is either unsubstituted of substituted with oneor more substituent(s) independently selected from the group consistingof halo, haloalkyl, carbonyl, carboxy, hydroxy, nitro, trifluoromethyl,C₁-C₆ straight or branched chain alkyl, C₂-C₆ straight or branched chainalkenyl, C₁-C₄ alkoxy, C₂-C₄ alkenyloxy, phenoxy, benzyloxy, thioalkyl,alkylthio, sulfhydryl, amino, alkylamino, aminoalkyl, aminocarboxyl, andAr₂;

[0167] R₁ is C₁-C₉ straight or branched chain alkyl, C₂-C₉ straight orbranched chain alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, or Ar₁,

[0168]  wherein said R₁ is unsubstituted or substituted with one or moresubstituents independently selected from the group consisting of C₁-C₆alkyl, C₂-C₆ alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, hydroxy, andAr₂;

[0169] Ar₁ and Ar₂ are independently an alicyclic or aromatic, mono-,bi- or tricyclic, carbo- or heterocyclic ring,

[0170]  wherein the ring is either unsubstituted or substituted with oneor more substituent (s), wherein the individual ring size is 5-8members,

[0171]  wherein said heterocyclic ring contains 1-6 heteroatom(s)independently selected from the group consisting of O, N, and S;

[0172] X is O, S, CH₂, or two hydrogen atoms;

[0173] Y is O or NR₂;

[0174] R₂ is hydrogen or C₁-C₆ alkyl;

[0175] Z is C₁-C₆ straight or branched chain alkyl or C₂-C₆ straight orbranched chain alkenyl,

[0176]  wherein said Z is substituted with one or more substituent(s)independently selected from the group consisting of Ar₁, C₃-C₈cycloalkyl, C₁-C₆ straight or branched chain alkyl substituted withC₃-C₈ cycloalkyl, and

[0177] C₂-C₆ straight or branched chain alkenyl, or Z is the fragment

[0178] wherein:

[0179] R₃ is C₁-C₉ straight or branched chain alkyl which isunsubstituted or substituted with C₃-C₈ cycloalkyl or Ar₁;

[0180] X₂ is O or NR₅;

[0181] R₅ is selected from the group consisting of hydrogen, C₁-C₆straight or branched chain alkyl, and C₂-C₆ straight or branched chainalkenyl; and

[0182] R₄ is selected from the group consisting of phenyl, benzyl, C₁-C₅straight or branched chain alkyl, C₂-C₅ straight or branched chainalkenyl, C₁-C₅ straight or branched chain alkyl substituted with phenyl,and C₂-C₅ straight or branched chain alkenyl substituted with phenyl.

[0183] All the compounds of Formulas I-V possess asymmetric centers andthus can be produced as mixtures of stereoisomers or as individual R-and S-stereoisomers. The individual stereoisomers may be obtained byusing an optically active starting material, by resolving a racemic ornon-racemic mixture of an intermediate at some appropriate stage of thesynthesis, or by resolving the compounds of Formulas I-V. It isunderstood that the compounds of Formulas I-V encompass individualstereoisomers as well as mixtures (racemic and non-racemic) ofstereoisomers. Preferably, S-stereoisomers are used in thepharmaceutical compositions and methods of the present invention.

Synthesis of Pyrrolidine Derivatives

[0184] The compounds of formulas I to V may be prepared by a variety ofsynthetic sequences that utilize established chemical transformations.The general pathway to the present compounds is described in Scheme I.N-glyoxylproline derivatives may be prepared by reacting L-prolinemethyl ester with methyl oxalyl chloride as shown in Scheme I. Theresulting oxamates may be reacted with a variety of carbon nucleophilesto obtain intermediates compounds. These intermediates are then reactedwith a variety of alcohols, amides, or protected amino acid residues toobtain the propyl esters and amides of the invention.

[0185] The substituted alcohols may be prepared by a number of methodsknown to those skilled in the art of organic synthesis. As described inScheme II, alkyl or aryl aldehydes may be homologated to phenylpropanols by reaction with methyl(triphenylphosphoranylidene)acetate toprovide a variety of trans-cinnamates; these latter may be reduced tothe saturated alcohols by reaction with excess lithium aluminum hydride,or sequentially by reduction of the double bond by catalytichydrogenation and reduction of the saturated ester by appropriatereducing agents. Alternatively, the trans-cinnamates may be reduced to(E)-allylic alcohols by the use of diisobutylaluminum hydride.

[0186] Longer chain alcohols may be prepared by homologation of benzylicand higher aldehydes. Alternatively, these aldehydes may be prepared byconversion of the corresponding phenylacetic and higher acids, andphenethyl and higher alcohols.

Affinity for FKBP12

[0187] The compounds used in the inventive methods and pharmaceuticalcompositions preferably have an affinity for the FK506 binding protein,particularly FKBP12. The inhibition of the prolyl peptidyl cis-transisomerase activity of FKBP may be measured as an indicator of thisaffinity.

K₁ Test Procedure

[0188] Inhibition of the peptidyl-prolyl isomerase (rotamase) activityof the compounds used in the inventive methods and pharmaceuticalcompositions can be evaluated by known methods described in theliterature (Harding et al., Nature, 1989, 341:758-760; Holt et al. J.Am. Chem. Soc., 115:9923-9938). These values are obtained as apparentK₁'s and are presented for representative compounds in TABLE I.

[0189] The cis-trans isomerization of an alanine-proline bond in a modelsubstrate, N-succinyl-Ala-Ala-Pro-Phe-p-nitroanilide, is monitoredspectrophotometrically in a chymotrypsin-coupled assay, which releasespara-nitroanilide from the trans form of the substrate. The inhibitionof this reaction caused by the addition of different concentrations ofinhibitor is determined, and the data is analyzed as a change infirst-order rate constant as a function of inhibitor concentration toyield the apparent K₁ values.

[0190] In a plastic cuvette are added 950 ml of ice cold assay buffer(25 mM HEPES, pH 7.8, 100 mM NaCl), 10 ml of FKBP (2.5 mM in 10 mMTris-Cl pH 7.5, 100 mM NaCl, 1 mM dithiothreitol), 25 ml of chymotrypsin(50 mg/ml in 1 mM HCl) and 10 ml of test compound at variousconcentrations in dimethyl sulfoxide. The reaction is initiated by theaddition of 5 ml of substrate(succinyl-Ala-Phe-Pro-Phe-para-nitroanilide, 5 mg/ml in 2.35 mM LiCl intrifluoroethanol).

[0191] The absorbance at 390 nm versus time is monitored for 90 secondsusing a spectrophotometer and the rate constants are determined from theabsorbance versus time data files. TABLE I In Vitro Test Results -Formulas I to V No. Z R₁ K_(i)  1 1,1-dimethylpropyl 3-phenylpropyl  42 2 ″ 3-phenyl-prop-2-(E)-enyl  125  3 ″ 3-(3,4,5-trimethoxy-  200phenyl)propyl  4 ″ 3-(3,4,5--trimethoxy-  65 phenyl)-prop-2-(E)-enyl  5″ 3-(4,5-methylenedioxy)-  170 phenylpropyl  6 ″ 3-(4,5-methylenedioxy) 160 phenylprop-2-(E)-enyl  7 ″ 3-cyclohexylpropyl  200  8 ″3-cyclohexylprop-2-(E)-enyl  600  9 ″ (1R)-1,3-diphenyl-1-propyl  52 102-furanyl 3-phenylpropyl 4000 11 2-thienyl ″  92 12 2-thiazolyl ″  10013 phenyl ″ 1970 14 1,1-dimethylpropyl 3-(2,5-dimethoxy)phenylpropyl 250 15 ″ 3-(2,5-dimethoxy)phenylprop- ″ 2-(E)-enyl  450 16 ″2-(3,4,5-trimethoxyphenyl)ethyl  120 17 ″ 3-(3-pyridyl)propyl   5 18 ″3-(2-pyridyl)propyl  195 19 ″ 3-(4-pyridyl)propyl  23 20 cyclohexyl3-phenylpropyl  82 21 tert-butyl ″  95 22 cyclohexylethyl ″ 1025 23cyclohexylethyl 3-(3-pyridyl)propyl 1400 24 tert-butyl3-(3-pyridyl)propyl   3 25 1,1-dimethylpropyl 3,3-diphenylpropyl   5 26cyclohexyl 3-(3-pyridyl)propyl   9 27 2-thienyl 3-(3-pyridyl)propyl 100028 tert-butyl 3,3-diphenylpropyl   5 29 cyclohexyl ″  20 30 2-thienyl3,3-diphenylpropyl  150

Route of Administration

[0192] To effectively treat alopecia or promote hair growth, thecompounds used in the inventive methods and pharmaceutical compositionsmust readily affect the targeted areas. For these purposes, thecompounds are preferably administered topically to the skin.

[0193] For topical application to the skin, the compounds can beformulated into suitable ointments containing the compounds suspended ordissolved in, for example, mixtures with one or more of the following:mineral oil, liquid petrolatum, white petrolatum, propylene glycol,polyoxyethylene polyoxypropylene compound, emulsifying wax and water.Alternatively, the compounds can be formulated into suitable lotions orcreams containing the active compound suspended or dissolved in, forexample, a mixture of one or more of the following: mineral oil,sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearylalcohol, 2-octyldodecanol, benzyl alcohol and water.

[0194] Other routes of administration known in the pharmaceutical artare also contemplated by this invention.

Dosage

[0195] Dosage levels on the order of about 0.1 mg to about 10,000 mg ofthe active ingredient compound are useful in the treatment of the aboveconditions, with preferred levels of about 0.1 mg to about 1,000 mg. Thespecific dose level for any particular patient will vary depending upona variety of factors, including the activity of the specific compoundemployed; the age, body weight, general health, sex and diet of thepatient; the time of administration; the rate of excretion; drugcombination; the severity of the particular disease being treated; andthe form of administration. Typically, in vitro dosage-effect resultsprovide useful guidance on the proper doses for patient administration.Studies in animal models are also helpful. The considerations fordetermining the proper dose levels are well known in the art.

[0196] The compounds can be administered with other hair revitalizingagents. Specific dose levels for the other hair revitalizing agents willdepend upon the factors previously stated and the effectiveness of thedrug combination.

EXAMPLES

[0197] The following examples are illustrative of the present inventionand are not intended to be limitations thereon. Unless otherwiseindicated, all percentages are based upon 100% by weight of the finalcomposition.

Example 1 Synthesis of(2S)-2-({1-oxo-5-phenyl}-pentyl-1-(3,3-dimethyl-1,2-dioxopentyl)pyrrolidine

[0198] (2S)-2-(1-oxo-4-phenyl)butyl-N-benzylpyrrolidine

[0199] 1-chloro-4-phenylbutane (1.78 g; 10.5 mmol) in 20 ml of THF wasadded to 0.24 g (10 mmol) of magnesium turnings in 50 ml of refluxingTHF. After the addition was complete, the mixture was refluxed for anadditional 5 hours, and then added slowly to a refluxing solution ofN-benzyl-L-proline ethyl ester (2.30 g (10 mmol) in 100 ml of THF. After2 hours of further reflux, the mixture was cooled and treated with 5 mlof 2 N HCl. The reaction mixture was diluted with ether (100 ml) andwashed with saturated NaHCO₃, water and brine. The organic phase wasdried, concentrated and chromatographed, eluting with 5:1 CH₂Cl₂:EtOActo obtain 2.05 g (64%) of the ketone as an oil. ¹H NMR (CDCl₃; 300 MHz):1.49-2.18 (m, 8H); 2.32-2.46 (m, 1H); 2.56-2.65 (m, 2H); 2.97-3.06 (m,1H); 3.17-3.34 (m, 1H); 3.44-3.62 (m, 1H); 4.02-4.23 (m, 2H); 7.01-7.44(m, 10H).

[0200] (2S)-2-(1-oxo-4-phenyl)butylpyrrolidine

[0201] The ketone compound (500 mg) and palladium hydroxide (20% oncarbon, 50 mg) was hydrogenated at 40 psi in a Paar shaker overnight.The catalyst was removed by filtration and the solvent was removed invacuo. The free amine was obtained as a yellow oil (230 mg; 100%). ¹HNMR (CDCl₃; 300 MHz): 1.75-2.34 (m, 10H); 2.55 (m, 2H); 2.95 (dm, 1H);3.45-3.95 (m, 1H); 4.05 (m, 1H); 7.37 (m, 5H).

[0202](2S)-2-(1-oxo-4-phenyl)butyl-1-(1,2-dioxo-2-methoxyethyl)pyrrolidine

[0203] To a solution of (2S)-2-(1-oxo-4-phenyl)butylpyrrolidine (230 mg;1.0 mmol) in CH₂Cl₂(20 ml) at 0° C. was added dropwise methyloxalylchloride (135 mg; 1.1 mmol). After stirring at 0° C. for 3 hours, thereaction was quenched with saturated NH₄Cl and the organic phase waswashed with water and brine and dried and concentrated. The cruderesidue was purified on a silica gel column, eluting with 20:1CH₂Cl₂:EtOAc to obtain 300 mg of the oxamate as a clear oil (98%). ¹HNMR (CDCl₃; 300 MHz): 1.68 (m, 4H); 1.91-2.38 (m, 4H); 2.64 (t, 2H);3.66-3.80 (m, 2H); 3.77, 3.85 (s, 3H total); 4.16 (m, 2H); 4.90 (m, 1H);7.16 (m, 3H); 7.27 (m, 2H).

[0204](2S)-2-({1-oxo-5-phenyl}-pentyl-1-(3,3-dimethyl-1,2-dioxopentyl)pyrrolidine

[0205] To a solution of the oxamate above (250 mg; 0.79 mmol) inanhydrous ether (15 ml), cooled to −78° C., was added1,1-dimethylpropyl-magnesium chloride (0.8 ml of a 1.0 M solution inether; 0.8 mmol). After stirring the resulting mixture at −78° C. for 2hours, the reaction was quenched by the addition of 2 ml of saturatedNH₄Cl, followed by 100 ml of EtOAc. The organic phase was washed withbrine, dried, concentrated, and purified on a silica gel column, elutingwith 50:1 CH₂Cl₂:EtOAc. The compound was obtained as a clear oil, 120mg. ¹H NMR (CDCl₃, 300 MHz): δ 0.87 (t, 3H,

=7.5); 1.22 (s, 3H); 1.25 (s, 3H); 1.67 (m, 4H); 1.70-2.33 (m, 6H); 2.61(t, 2H,

=7.1); 3.52 (m, 2H); 4.17 (t, 2H,

=6.2); 4.52 (m, 1H); 7.16-7.49 (m, 5H). Analysis calculated forC₂₂H₃₁NO₃—H₂O: C, 70.37; H, 8.86; N, 3.73. Found: 70.48; H, 8.35; N,3.69.

Example 2 Synthesis of 2-phenyl-1-ethyl1-(3,3-dimethyl-1,2-dioxopentyl)-2-piperidinecarbothioate

[0206] Methyl(2S)-1-(1,2-dioxo-2-methoxyethyl)-2-pyrrolidinecarboxylate

[0207] A solution of L-proline methyl ester hydrochloride (3.08 g; 18.60mmol) in dry methylene chloride was cooled to 0° C. and treated withtriethylamine (3.92 g; 38.74 mmol; 2.1 eq). After stirring the formedslurry under a nitrogen atmosphere for 15 min, a solution of methyloxalyl chloride (3.20 g; 26.12 mmol) in methylene chloride (45 ml) wasadded dropwise. The resulting mixture was stirred at 0° C. for 1,5 hour.After filtering to remove solids, the organic phase was washed withwater, dried over MgSO₄ and concentrated. The crude residue was purifiedon a silica gel column, eluting with 50% ethyl acetate in hexane, toobtain 3.52 g (88%) of the product as a reddish oil. Mixture ofcis-trans amide rotamers; data for trans rotamer given. ¹H NMR (CDCl₃):δ 1.93 (dm, 2H); 2.17 (m, 2H); 3.62 (m, 2H); 3.71 (s, 3H) 3.79, 3.84 (s,3H total); 4.86 (dd, 1H,

=8.4, 3.3).

[0208]Methyl(2S)-1-(1,2-dioxo-3,3-dimethylpentyl)-2-pyrrolidinecarboxylate

[0209] A solution of methyl(2S)-1-(1,2-dioxo-2-methoxyethyl)-2-pyrrolidinecarboxylate (2.35 g;10.90 mmol) in 30 ml of tetrahydrofuran (THF) was cooled to −78° C. andtreated with 14.2 ml of a 1.0 M solution of 1,1-dimethylpropylmagnesiumchloride in THF. After stirring the resulting homogeneous mixture at−78° C. for three hours, the mixture was poured into saturated ammoniumchloride (100 ml) and extracted into ethyl acetate. The organic phasewas washed with water, dried, and concentrated, and the crude materialobtained upon removal of the solvent was purified on a silica gelcolumn, eluting with 25% ethyl acetate in hexane, to obtain 2.10 g (75%)of the oxamate as a colorless oil. ¹H NMR (CDCl₃): δ 0.88 (t, 3H); 1.22,1.26 (s, 3H each); 1.75(dm, 2H); 1.87-2.10 (m, 3H); 2.23 (m, 1H); 3.54(m, 2H); 3.76 (s, 3H); 4.52 (dm, 1H,

=8.4, 3.4).

[0210] (2S)-1-(1,2-dioxo-3,3-dimethylpentyl)-2-pyrrolidinecarboxylicAcid

[0211] A mixture of methyl(2S)-1-(1,2-dioxo-3,3-dimethylpentyl)-2-pyrrolidinecarboxylate (2.10 g;8.23 mmol), 1 N LIOH (15 ml), and methanol (50 ml) was stirred at 0° C.for 30 minutes and at room temperature overnight. The mixture wasacidified to pH 1 with 1 N HCl, diluted with water, and extracted into100 ml of methylene chloride. The organic extract was washed with brineand concentrated to deliver 1.73 g (87%) of snow-white solid which didnot require further purification. ¹H NMR (CDCl₃): δ 0.87 (t, 3H); 1.22,1.25 (s, 3H each); 1.77 (dm, 2H); 2.02 (m, 2H); 2.17 (m, 1H); 2.25 (m,1H); 3.53 (dd, 2H,

=10.4, 7.3); 4.55 (dd, 1H,

=8.6, 4.1).

[0212] 2-phenyl-1-ethyl1-(3,3-dimethyl-1,2-dioxopentyl)-2-piperidinecarbothioate

[0213] To a solution of(2S)-1-(1,2-dioxo-3,3-dimethylpentyl)-2-pyrrolidinecarboxylic acid (241mg; 1.0 mmol) in CH₂Cl₂ (10 ml) was added dicyclohexylcarbo-diimide (226mg; 1.1 mmol). After stirring the resulting mixture for 5 minutes, thesolution was cooled to 0° C. and treated with a solution of phenylmercaptan (138 mg; 1.0 mmol) and 4-dimethylaminopyridine (6 mg) in 5 mlof CH₂Cl₂. The mixture was allowed to warm to room temperature withstirring overnight. The solids were removed by filtration and thefiltrate was concentrated in vacuo; the crude residue was purified byflash chromatography (10:1 hexane:EtOAc) to obtain 302 mg (84%) of thecompound as an oil. ¹H NMR (CDCl₃, 300 MHz): δ 0.85 (t, 3H,

=7.5); 1.29 (s, 3H); 1.31 (s, 3H); 1.70-2.32 (m, 6H); 2.92 (t, 2H,

=7.4); 3.22(t, 2H,

=7.4); 3.58 (m, 2H); 4.72 (m, 1H); 7.23-7.34 (m, 5H). Analysiscalculated for C₂₀H₂₇NO₃S—0.4H₂O: C, 65.15; H, 7.60; N, 3.80. Found: C,65.41; H, 7.49; N, 3.72.

Example 3 Synthesis of 2-phenyl-1-ethyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate

[0214] Methyl 1-(1,2-dioxo-2-methoxyethyl)-2-piperidinecarboxylate

[0215] A solution of methyl pipecolate hydrochloride (8.50 g; 47.31mmol) in dry methylene chloride (100 ml) was cooled to 0° C. and treatedwith triethylamine (10.5 g; 103 mmol; 2.1 eq). After stirring the formedslurry under a nitrogen atmosphere for 15 minutes, a solution of methyloxalyl chloride (8.50 g; 69.4 mmol) in methylene chloride (75 ml) wasadded dropwise. The resulting mixture was stirred at 0° C. for 1,5hours. After filtering to remove solids, the organic phase was washedwith water, dried over MgSO₄ and concentrated. The crude residue waspurified on a silica gel column, eluting with 50% ethyl acetate inhexane, to obtain 9.34 g (86%) of the product as a reddish oil. Mixtureof cis-trans amide rotamers; data for trans rotamer given. ¹H NMR(CDCl₃): δ 1.22-1.45 (m, 2H); 1.67-1.78 (m, 3H); 2.29 (m, 1H); 3.33 (m,1H); 3.55 (m, 1H); 3.76 (s, 3H); 3.85, 3.87 (s, 3H total); 4.52 (dd,1H).

[0216] Methyl 1-(1,2-dioxo-3,3-dimethylpentyl)-2-piperidinecarboxylate

[0217] A solution of methyl1-(1,2-dioxo-2-methoxyethyl)-2-piperidinecarboxylate (3.80 g; 16.57mmol) in 75 ml of tetrahydrofuran (THF) was cooled to −78° C. andtreated with 20.7 ml of a 1.0 M solution of 1,1-dimethyl-propylmagnesiumchloride in THF. After stirring the resulting homogeneous mixture at−78° C. for three hours, the mixture was poured into saturated ammoniumchloride (100 ml) and extracted into ethyl acetate. The organic phasewas washed with water, dried, and concentrated, and the crude materialobtained upon removal of the solvent was purified on a silica gelcolumn, eluting with 25% ethyl acetate in hexane, to obtain 3.32 g (74%)of the oxamate as a colorless oil. ¹H NMR (CDCl₃): δ 0.88 (t, 3H); 1.21,1.25 (s, 3H each); 1.35-1.80 (m, 7H); 2.35 (m, 1H); 3.24 (m, 1H); 3.41(m, 1H); 3.76 (s, 3H); 5.32 (d, 1H).

[0218] 1-(1,2-dioxo-3,3-dimethylpentyl)-2-piperidinecarboxylic Acid

[0219] A mixture of methyl1-(1,2-dioxo-3,3-dimethylpentyl)-2-piperidinecarboxylate (3.30 g; 12.25mmol), 1 N LiOH (15 ml), and methanol (60 ml) was stirred at 0° C. for30 minutes and at room temperature overnight. The mixture was acidifiedto pH 1 with 1 N HCl, diluted with water, and extracted into 100 ml ofmethylene chloride. The organic extract was washed with brine andconcentrated to deliver 2.80 g (87%) of snow-white solid which did notrequire further purification. ¹H NMR (CDCl₃): δ 0.89 (t, 3H); 1.21, 1.24(s, 3H each); 1.42-1.85 (m, 7H); 2.35 (m, 1H); 3.22 (d, 1H); 3.42(m,1H); 5.31 (d, 1H).

[0220] 2-phenyl-1-ethyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarbothioate

[0221] To a solution of1-(1,2-dioxo-3,3-dimethylpentyl)-2-piperidine-carboxylic acid (255 mg;1.0 mmol) in CH₂Cl₂ (10 ml) was added dicyclohexylcarbodiimide (226 mg;1.1 mmol). After stirring the resulting mixture for 5 minutes, thesolution was cooled to 0° C. and treated with a solution of phenylmercaptan (138 mg; 1.0 mmol) and 4-dimethylaminopyridine (6 mg) in 5 mlof CH₂Cl₂. The mixture was allowed to warm to room temperature withstirring overnight. The solids were removed by filtration and thefiltrate was concentrated in vacuo; the crude residue was purified byflash chromatography (10:1 hexane:EtOAc) to obtain 300 mg (80%) of thecompound as an oil. ¹H NMR (CDCl₃, 300 MHz): d 0.94 (t, 3H,

=7.5); 1.27 (s, 3H); 1.30 (s, 3H); 1.34-1.88 (m, 7H); 2.45 (m, 1H); 2.90(t, 2H,

=7.7); 3.26 (t, 2H,

=7.7); 3.27 (m, 1H); 3.38 (m, 1H); 5.34 (m, 1H); 7.24-7.36 (m, 5H).Analysis calculated for C₂₁H₂₉NO₃S: C, 67.17; H, 7.78; N, 3.73. Found:C, 67.02; H, 7.83; N, 3.78.

Example 4 Synthesis of3-phenyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-(4-thiazolidine)carboxylate

[0222] 1-(1,2-dioxo-2-methoxyethyl)2-(4-thiazolidine)carboxylate

[0223] A solution of L-thioproline (1.51 g; 11.34 mmol) in 40 ml of drymethylene chloride was cooled to 0° C. and treated with 3.3 ml (2.41 g;23,81 mmol) of triethylamine. After stirring this mixture for 30minutes, a solution of methyl oxalyl chloride (1.81 g; 14.74 mmol) wasadded dropwise. The resulting mixture was stirred at 0° C. for 1.5hours, filtered through Celite to remove solids, dried and concentrated.The crude material was purified on a silica gel column, eluting with 10%MeOH in methylene chloride, to obtain 2.0 g of the oxamate as anorange-yellow solid.

[0224] 3-phenyl-1-propyl (2S)-1-(1,2-dioxo-2-methoxyethyl)2-(4-thiazolidine)carboxylate

[0225] 1-(1,2-dioxo-2-methoxyethyl)2-(4-thiazolidine)carboxylate (500mg; 2.25 mmol), 3-phenyl-1-propanol (465 mg; 3.42 mmol),dicyclohexylcarbodiimide (750 mg; 3.65 mmol), 4-dimethylaminopyridine(95 mg; 0.75 mmol) and camphorsulfonic acid (175 mg; 0.75 mmol) in 30 mlof methylene chloride were stirred together overnight. The mixture wasfiltered through Celite to remove solids and chromatographed (25% ethylacetate/hexane) to obtain 690 mg of material. ¹H NMR (CDCl₃, 300 MHz)δ1.92-2.01 (m, 2H); 2.61-2.69 (m, 2H); 3.34 (m, 1H); 4.11-4.25 (m, 2H);4.73 (m, 1H); 5.34 (m, 1H); 7.12 (m, 3H); 7.23 (m, 2H).

[0226]3-phenyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-(4-thiazolidine)carboxylate

[0227] A solution of 3-phenyl-1-propyl(2S)-1-(1,2-dioxo-2-methoxyethyl)2-(4-thiazolidine)carboxylate (670 mg;1.98 mmol) in tetrahydrofuran (10 ml) was cooled to −78° C. and treatedwith 2.3 ml of a 1.0 M solution of 1,1-dimethylpropylmagnesium chloridein ether. After stirring the mixture for 3 hours, it was poured intosaturated ammonium chloride, extracted into ethyl acetate, and theorganic phase was washed with water, dried and concentrated. The crudematerial was purified on a silica gel column, eluting with 25% ethylacetate in hexane, to obtain 380 mg of the compound as a yellow oil. ¹HNMR (CDCl, 300 MHz): d 0.86 (t, 3H); 1.21 (s, 3H); 1.26 (s, 3H);1.62-1.91 (m, 3H); 2.01 (m, 2H); 2.71 (m, 2H); 3.26-3.33 (m, 2H); 4.19(m, 2H); 4.58 (m, 1H); 7.19 (m, 3H); 7.30 (m, 2H). Analysis calculatedfor C₂₀H₂₇NO₄S: C, 63.63; H, 7.23; N, 3.71. Found: C, 64.29; H, 7.39; N,3.46.

Example 5 Synthesis of3-(3-pyridyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-(4-thiazolidine)carboxylate

[0228] The compound of Example 5 was prepared according to the procedureof Example 4, using 3-(3-pyridyl)-1-propanol in the final step, to yield3-(3-pyridyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-(4-thiazolidine)carboxylate.¹H NMR (CDCl₃, 300 MHz): δ 0.89 (t, 3H,

=7.3); 1.25 (s, 3H); 1.28 (s, 3H); 1.77 (q, 2H,

=7.3); 2.03 (tt, 2H,

=6.4, 7.5); 2.72 (t, 2H,

=7.5); 3.20 (dd, 1H,

=4.0, 11.8); 3.23 (dd, 1H,

=7.0, 11.8); 4.23 (t, 2H,

=6.4); 4.55 (d, 2H,

=8.9); 5.08 (dd, 1H,

=4.0, 7.0); 7.24 (m, 1H); 8.48 (m, 2H). Analysis calculated forC₁₉H₂₆N₂O₄S—0.5 H₂O: C, 58.89; H, 7.02; N, 7.23. Found: C, 58.83; H,7.05; N, 7.19.

Example 6 Synthesis of 3-(3-pyridyl)-1-propyl(2S)-1-(3,3-Dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate, N-oxide

[0229] Methyl (2S)-1-(1,2-dioxo-2-methoxyethyl)-2-pyrrolidinecarboxylate

[0230] A solution of L-proline methyl ester hydrochloride (3.08 g; 18.60mmol) in dry methylene chloride was cooled to 0° C. and treated withtriethylamine (3.92 g; 38.74 mmol; 2.1 eq). After stirring the formedslurry under a nitrogen atmosphere for 15 minutes, a solution of methyloxalyl chloride (3.20 g; 26.12 mmol) in methylene chloride (45 ml) wasadded dropwise. The resulting mixture was stirred at 0° C. for 1.5 hour.After filtering to remove solids, the organic phase was washed withwater, dried over MgSO₄ and concentrated. The crude residue was purifiedon a silica gel column, eluting with 50% ethyl acetate in hexane, toobtain 3.52 g (88%) of the product as a reddish oil. Mixture ofcis-trans amide rotamers; data for trans rotamer given. ¹H NMR (CDCl₃):δ 1.93 (dm, 2H); 2.17 (m, 2H); 3.62 (m, 2H); 3.71 (s, 3H); 3.79, 3.84(s, 3H total); 4.86 (dd, 1H,

=8.4, 3.3).

[0231]Methyl(2S)-1-(1,2-dioxo-3,3-dimethylpentyl)-2-pyrrolidinecarboxylate

[0232] A solution of methyl(2S)-1-(1,2-dioxo-2-methoxyethyl)-2-pyrrolidinecarboxylate (2.35 g;10.90 mmol) in 30 ml of tetrahydrofuran (THF) was cooled to −78° C. andtreated with 14.2 ml of a 1.0 M solution of 1,1-dimethylpropylmagnesiumchloride in THF. After stirring the resulting homogeneous mixture at−78° C. for three hours, the mixture was poured into saturated ammoniumchloride (100 ml) and extracted into ethyl acetate. The organic phasewas washed with water, dried, and concentrated, and the crude materialobtained upon removal of the solvent was purified on a silica gelcolumn, eluting with 25% ethyl acetate in hexane, to obtain 2.10 g (75%)of the oxamate as a colorless oil. ¹H NMR (CDCl₃): δ 0.88 (t, 3H); 1.22,1.26 (s, 3H each); 1.75 (dm, 2H); 1.87-2.10 (m, 3H); 2.23 (m, 1H); 3.54(m, 2H); 3.76 (s, 3H); 4.52 (dm, 1H,

=8.4, 3.4).

[0233] (2S)-1-(1,2-dioxo-3,3-dimethylpentyl)-2-pyrrolidinecarboxylicAcid

[0234] A mixture of methyl(2S)-1-(1,2-dioxo-3,3-dimethylpentyl-2-pyrrolidine-carboxylate (2.10 g;8.23 mmol), 1 N LiOH (15 ml), and methanol (50 ml) was stirred at 0° C.for 30 minutes and at room temperature overnight. The mixture wasacidified to pH 1 with 1 N HCl, diluted with water, and extracted into100 ml of methylene chloride. The organic extract was washed with brineand concentrated to deliver 1.73 g (87%) of snow-white solid which didnot require further purification. ¹H NMR (CDCl₃): d 0.87 (t, 3H); 1.22,1.25 (s, 3H each); 1.77 (dm, 2H); 2.02 (m, 2H); 2.17 (m, 1H); 2.25 (m,1H); 3.53 (dd, 2H,

=10.4, 7.3); 4.55 (dd, 1H,

=8.6, 4.1).

[0235]3-(3-Pyridyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate

[0236] A mixture of(2S)-1-(1,2-dioxo-3,3-dimethylpentyl)-2-pyrrolidinecarboxylic acid (4.58g; 19 mmol), 3-pyridinepropanol (3.91 g; 28.5 mmol),dicyclohexylcarbodiimide (6.27 g; 30.4 mmol), camphorsulfonic acid (1.47g; 6.33 mmol) and 4-dimethyl aminopyridine (773 mg; 6.33 mmol) inmethylene chloride (100 ml) was stirred overnight under a nitrogenatmosphere. The reaction mixture was filtered through Celite to removesolids and concentrated in vacuo. The crude material was triturated withseveral portions of ether, and the ether portions were filtered throughCelite to remove solids and concentrated in vacuo. The concentratedfiltrate was purified on a flash column (gradient elution, 25% ethylacetate in hexane to pure ethyl acetate) to obtain 5.47 g (80%) of GPI1046 as a colorless oil (partial hydrate). ¹H NMR (CDCl₃, 300 MHz): δ0.85 (t, 3H); 1.23, 1.26 (s, 3H each); 1.63-1.89 (m, 2H); 1.90-2.30 (m,4H); 2.30-2.50 (m, 1H); 2.72 (t, 2H); 3.53 (m, 2H); 4.19 (m, 2H); 4.53(m, 1H); 7.22 (m, 1H); 7.53 (dd, 1H); 8.45. Analysis calculated forC₂₀H₂₈NO₄—0.25H₂O: C, 65.82; H, 7.87; N, 7.68. Found: C, 66.01; H, 7.85;N, 7.64.

[0237] 3-(3-Pyridyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate, N-oxide

[0238] A solution of 3-(3-pyridyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate (190 mg;0.52 mmol) and m-chloroperbenzoic acid (160 mg of 57%-86% material, 0.53mmol) was stirred in methylene chloride (20 ml) at room temperature for3 hours. The reaction mixture was diluted with methylene chloride andwashed twice with 1 N NaOH. The organic extract was dried andconcentrated, and the crude material was chromatographed, eluting with10% methanol in ethyl acetate, to obtain 130 mg of the Compound ofExample 6. ¹H NMR (CDCl₃, 300 MHz): δ 0.83 (t, 3H); 1.21 (s, 3H); 1.25(s, 3H); 1.75-2.23 (m, 8H); 2.69 (t, 2H,

=7.5); 3.52 (t, 2H,

=6.3); 4.17 (dd, 2H,

=6.3); 4.51 (m, 1H); 7.16-7.22 (m, 2H); 8.06-8.11 (m, 2H). Analysiscalculated for C₂₀H₂₈N₂O₅—0.75H₂O: C, 61.60; H, 7.63; N, 7.18. Found: C,61.79; H, 7.58; N, 7.23.

Example 7 Synthesis of 3-(3-Pyridyl)-1-propylmercaptyl2S-1-[(2-methylbutyl)carbamoyl]pyrrolidine-2-carboxylate

[0239] 3-(3-Pyridyl)-1-propylchloride

[0240] To a solution of 3-(3-pyridyl)-1-propanol (10 g; 72.4 mmol) inchloroform (100 ml) was added dropwise a solution of thionyl chloride(12.9 g; 108.6 mmol) in chloroform (50 ml). The resulting mixture wasrefluxed for 1 hour, then poured into ice-cold 50% aqueous potassiumhydroxide (150 ml). The layers were separated, and the organic phase wasdried, concentrated, and purified on a silica gel column, eluting with40% ethylacetate in hexane, to obtain 10 g (65%) of the chloride as aclear oil. ¹H NMR (300 MHz, CDCl₃): δ 2.02-2.11 (m, 2H); 2.77 (m, 2H);3.51 (m, 2H); 7.20 (m, 1H); 7.49 (m, 1H); 8.45 (m, 2H).

[0241] 3-(3-Pyridyl)-1-propylmercaptan

[0242] A mixture of 3-(3-pyridyl)-1-propylchloride (3 g; 19.4 mmol) andthiourea (1.48 g; 19.4 mmol) in ethanol (10 ml) was refluxed for 24hours. Aqueous sodium hydroxide, 15 ml of a 0.75 N solution, was added,and the mixture was refluxed for an additional 2 hours. After cooling toroom temperature, the solvent was removed in vacuo. Chromatographicpurification of the crude thiol on a silica gel column eluting with 50%ethyl acetate in hexane delivered 1.2 g of3-(3-Pyridyl)-1-propylmercaptan as a clear liquid. ¹H NMR (300 MHz,CDCl₃): δ 1.34 (m, 1H); 1.90 (m, 2H); 2.52 (m, 2H); 2.71 (m, 2H); 7.81(m, 1H); 7.47 (m, 1H) 8.42 (m, 2H).

[0243] 3-(3-Pyridyl)-1-propylmercaptylN-(tert-butyloxycarbonyl)pyrrolidine-2-carboxylate

[0244] A mixture of N-(tert-butyloxycarbonyl)-(S)-proline (3.0 g; 13.9mmol); 3-(3-Pyridyl)-1-propylmercaptan (3.20 g; 20.9 mmol),dicyclohexylcarbodiimide (4.59 g; 22.24 mmol), camphorsulfonic acid(1.08 g; 4.63 mmol), and 4-dimethylaminopyridine (0.60 g; 4.63 mmol) indry methylene chloride (100 ml) was stirred overnight. The reactionmixture was diluted with methylene chloride (50 ml) and water (100 ml),and the layers were separated. The organic phase was washed with water(3×100 ml), dried over magnesium sulfate, and concentrated, and thecrude residue was purified on a silica gel column eluting with ethylacetate to obtain 4.60 g (95%) of the thioester as a thick oil. ¹H NMR(300 MHz, CDCl₃): δ 1.45 (s, 9H); 1.70-2.05 (m, 5H); 2.32 (m, 1H); 2.71(t, 2H); 2.85 (m, 2H); 3.50 (m, 2H); 4.18 (m, 1H); 7.24 (m, 1H); 7.51(m, 1H); 8.48 (m, 2H).

[0245] 3-(3-Pyridyl)-1-propylmercaptyl pyrrolidine-2-carboxylate

[0246] A solution of 3-(3-Pyridyl)-1-mercaptylN-(tert-butyloxycarbonyl)pyrrolidine-2-carboxylate (4.60 g; 13.1 mmol)in methylene chloride (60 ml) and trifluoroacetic acid (6 ml) wasstirred at room temperature for three hours. Saturated potassiumcarbonate was added until the pH was basic, and the reaction mixture wasextracted with methylene chloride (3×). The combined organic extractswere dried and concentrated to yield 2.36 g (75%) of the free amine as athick oil. ¹H NMR (300 MHz, CDCl₃): δ 1.87-2.20 (m, 6H); 2.79 (m, 2H);3.03-3.15 (m, 4H total); 3.84 (m, 1H); 7.32 (m, 1H); 7.60 (m, 1H); 8.57(m, 2H).

[0247] 3-(3-Pyridyl)-1-propylmercaptyl2S-1-[(2-methylbutyl)carbamoyl]pyrrolidine-2-carboxylate (101)

[0248] A solution of 2-methylbutylamine (113 mg; 1.3 mmol) andtriethylamine (132 mg; 1.3 mmol) in methylene chloride (5 ml) was addedto a solution of triphosgene (128 mg; 0.43 mmol) in methylene chloride(5 ml). The resulting mixture was refluxed for 1 hour and then cooled toroom temperature. 3-(3-Pyridyl)-1-propylmercaptylpyrrolidine-2-carboxylate (300 mg; 1.3 mmol) in 5 ml of methylenechloride was added and the resulting mixture was stirred for 1 hour andthen partitioned between water and a 1:1 mixture of ethyl acetate andhexane. The organic phase was dried, concentrated and purified by columnchromatography (50% ethyl acetate/hexane) to obtain 250 mg (55%) of thecompound of Example 7 as an oil. ¹H NMR (300 MHz, CDCl₃): d ¹H NMR(CDCl₃, 300 MHz): δ 0.89-0.93 (m, 6H); 1.10-1.20 (m, 1H); 1.27 (s, 1H);1.36-1.60 (m, 2H); 1.72 (s, 2H); 1.97-2.28 (m, 6H); 2.70-2.75 (m, 2H);2.92-3.54 (m, 6H); 4.45-4.47 (m, 1H); 7.21-7.29 (m, 1H); 7.53-7.56 (dd,1H); 8.46-8.48 (s, 2H).

Example 8 Synthesis of 3-(3-Pyridyl)-1-propyl2S-1-[(1′,1′-Dimethylpropyl)carbamoyl]-pyrrolidine-2-carboxylate

[0249] Reaction of 3-(3-pyridyl)-1-propylmercaptylpyrrolidine-2-carboxylate with the isocyanate generated fromtert-amylamine and triphosgene, as described for Example 7, provided thecompound of Example 8 in 62% yield. ¹H NMR (CDCl₃, 300 MHz): δ 0.83 (t,3H); 1.27 (s, 6H); 1.64-1.71 (m, 2H); 1.91-2.02 (m, 7H); 2.66-2.71 (t,2H); 2.85 (m, 2H); 3.29-3.42 (m, 2H); 4.11 (br, 1H); 4.37-4.41 (m, 1H)

Example 9 Synthesis of 3-(3-pyridyl)-1-propylmercaptyl2S-1-[(cyclohexyl)thiocarbamoyl]-pyrrolidine-2-carboxylate

[0250] A mixture of cyclohexylisothiocyanate (120 mg; 0.9 mmol),3-(3-pyridyl)-1-propylmercaptyl pyrrolidine-2-carboxylate (200 mg; 0.9mmol) and triethylamine (90 mg; 0.9 mmol) in 20 ml of methylene chloridewas stirred for 1 hour and then partitioned between water and a 1:1mixture of ethyl acetate and hexane. The organic phase was dried,concentrated and purified by column chromatography (50% ethylacetate/hexane) to obtain 160 mg (47%) of the compound of Example 9. ¹HNMR (CDCl₃, 300 MHz) δ 1.16-1.40 (m, 6H); 1.50-1.71 (m, 4H); 1.95-2.08(m, 7H); 2.70-2.75 (t, 2H); 3.03 (m, 2H); 3.40-3.60 (m, 2H); 4.95-4.98(d, 1H); 5.26-5.29 (d, 1H); 7.17-7.25 (m, 1H).

Example 10 Synthesis of3-(para-Methoxyphenyl)-1-propylmercaptyl(2S)-N-(benzenesulfonyl)pyrrolidine-2-carboxylate

[0251] 3-(p-Methoxyphenyl)-1-propylbromide

[0252] To a solution of 3-(p-methoxyphenyl)-1-propanol (16.6 g; 0.1 mol)in 250 ml of toluene, cooled to 0° C., was added dropwise 26 ml ofphosphorus tribromide (0.27 mol). Following completion of the addition,the reaction was stirred at room temperature for 1 hour, then refluxedfor an additional hour. The reaction was cooled and poured onto ice, thelayers were separated, and the organic phase washed with saturatedsodium bicarbonate (3×) and brine (3×). The crude material obtained upondrying and evaporation of the solvent was chromatographed, eluting with10% EtOAc/hexane, to obtain 14 g (61%) of3-(p-methoxyphenyl)-1-propylbromide.

[0253] 3-(p-Methoxyphenyl)-1-propylmercaptan

[0254] A mixture of 3-(p-methoxyphenyl)-1-propylbromide (14 g; 61 mmol)and thiourea (5.1 g; 67 mmol) in ethanol (150 ml) was refluxed for 48hours. Evaporation of the solvent provided a clear glassy compound,which was dissolved in 50 ml of water and treated with 100 ml of 40%aqueous sodium hydroxide. After stirring the resulting mixture for twohours, the product was extracted into ether (3×), and the combinedorganic extracts were washed with sodium bicarbonate and brine, dried,and concentrated. Chromatographic purification of the crude thiol on asilica gel column eluting with 2% either in hexane delivered 10.2 g of3-(p-methoxyphenyl)-1-propylmercaptan as a clear liquid. ¹H NMR (300MHz, CDCl₃): δ 1.34 (t, 1H); 1.88-1.92 (m, 2H); 2.49-2.53 (m, 2H);2.64-2.69 (m, 2H); 3.77 (s, 3H); 6.80-6.84 (m, 2H); 7.06-7.24 (m, 2H).

[0255] 3-(p-Methoxyphenyl)-1-mercaptylN-(tert-butyloxycarbonyl)pyrrolidine-2-carboxylate

[0256] A mixture of N-(tert-butyloxycarbonyl)-(S)-proline (2.0 g; 9.29mmol), 3-(p-methoxyphenyl)-1-propylmercaptan (1.86 g; 10.22 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.96 g;10.22 mmol), and 4-dimethylaminopyridine (catalytic) in dry methylenechloride (50 ml) was stirred overnight. The reaction mixture was dilutedwith methylene chloride (50 ml) and water 100 (ml), and the layers wereseparated. The organic phase was washed with water (3×100 ml), driedover magnesium sulfate, and concentrated to provide 3.05 g of theproduct (100%) as a thick oil. ¹H NMR (300 MHz, CDCl₃): δ 1.15 (s, 9H);1.84-2.31 (m, 6H); 2.61 (m, 2H); 2.83 (m, 2H); 3.51 (m, 2H); 3.75 (s,3H); 6.79 (d, 2H,

=8.04); 7.05 (m, 2H).

[0257] 3-(p-Methoxyphenyl)-1-mercaptyl pyrrolidine-2-carboxylate

[0258] A solution of 3-(p-methoxyphenyl)-mercaptylN-(tert-butyloxycarbonyl)pyrrolidine-2-carboxylate (3.0 g; 8.94 mmol) inmethylene chloride (60 ml) and trifluoroacetic acid (6 ml) was stirredat room temperature for three hours. Saturated potassium carbonate wasadded until the pH was basic, and the reaction mixture was extractedwith methylene chloride (3×). The combined organic extracts were driedand concentrated to yield 1.73 g (69%) of the free amine as a thick oil.¹H NMR (300 MHz, CDCl₃): δ 1.80-2.23 (m, 6H); 2.62 (m, 2H); 2.81 (m,2H); 3.01 (m, 2H); 3.75 (s, 3H); 3.89(m, 1H); 6.81 (m, 2H); 7.06 (m,2H).

[0259] 3-(para-Methoxyphenyl)-1-propylmercaptyl(2S)-N-(benzenesulfonyl)pyrrolidine-2-carboxylate

[0260] A solution of 3-(p-methoxyphenyl)-1-mercaptylpyrrolidine-2-carboxylate (567 mg; 2.03 mmol) and benzenesulfonylchloride (358 mg; 2.03 mmol) in methylene chloride (5 ml) was treatedwith diisopropylethylamine (290 mg; 2.23 mmol) and stirred overnight atroom temperature. The reaction mixture was filtered to remove solids andapplied directly to a silica gel column, eluting with 25% ethyl acetatein hexane, to obtain 540 mg of the compound as a clear oil. ¹H NMR (300MHz, CDCl₃): δ 1.65-1.89 (m, 6H); 2.61 (t, 2H,

=7.3); 2.87 (t, 2H,

=7.6); 3.26 (m, 1H); 3.54 (m, 1H); 3.76 (s, 3H); 4.34 (dd, 1H,

=2.7, 8.6); 6.79 (d, 2H,

=8.7); 7.06 (d, 2H,

=8.6); 7.49-7.59 (m, 3H); 7.86 (dd, 2H,

=1.5, 6.8).

Example 11 Synthesis of 3-(para-Methoxyphenyl)-1-propylmercaptyl(2S)-N-(α-toluenesulfonyl) pyrrolidine-2-carboxylate

[0261] A solution of 3-(p-Methoxyphenyl)-1-mercaptylpyrrolidine-2-carboxylate (645 mg; 2.30 mmol) and α-toluenesulfonylchloride (440 mg; 2.30 mmol) in methylene chloride (5 ml) was treatedwith diisopropylethylamine (330 mg; 2.53 mmol) and stirred overnight atroom temperature. Purification as described for Example 10 provided thecompound of Example 11 as a clear oil. ¹H NMR (300 MHz, CDCl₃): δ1.65-2.25 (m, 8H); 2.65 (t, 2H); 2.89-2.96 (m, 2H); 3. 55-3.73 (m, 2H);3.80 (s, 3H); 4.32 (s, 2H); 4.70-4.81 (m, 1H); 6.83 (d, 2H); 7.09 (d,2H); 7.14 (m, 3H); 7.26 (m, 2H).

Example 12 Synthesis of 3-(para-Methoxyphenyl)-1-propylmercaptyl(2S)-N-(α-toluenesulfonyl)-pyrrolidine-2-carboxylate

[0262] A solution of 3-(p-methoxyphenyl)-1-mercaptylpyrrolidine-2-carboxylate (567 mg; 2.30 mmol) and p-toluenesulfonylchloride (425 mg; 2.23 mmol) in methylene chloride (5 ml) was stirredovernight at room temperature. Purification as described for Example 10provided the compound of Example 12 as a clear oil. ¹H NMR (300 MHz,CDCl₃): δ 1.67-1.94 (m, 6H); 2.40 (s, 3H); 2.61 (t, 2H,

=7.3); 2.84 (m, 2H,

=7.2); 3.22 (m, 1H); 3.52 (m, 1H); 3.76 (s, 3H); 4.32 (dd, 1H, J-2.9,8.5); 6.79 (d, 2H,

=6.5); 7.07 (d, 2H,

=6.5); 7.29 (d, 2H,

=6.5); 7.74 (d, 2H,

=6.5).

Example 13 Synthesis of 1,5-Diphenyl-3-pentylmercaptylN-(para-toluenesulfonyl)pipecolate

[0263] 3-Phenyl-1-propanal

[0264] Oxalyl chloride (2.90 g; 2.29 mmol) in methylene chloride (50ml), cooled to −78° C., was treated with dimethylsulfoxide (3.4 ml) in10 ml of methylene chloride. After stirring for 5 min,3-phenyl-1-propanol (2.72 g; 20 mmol) in 20 ml of methylene chloride wasadded, and the resulting mixture was stirred at −78° C. for 15 min,treated with 14 ml of triethylamine, stirred an additional 15 min, andpoured into 100 ml of water. The layers were separated, the organicphase was dried and concentrated, and the crude residue was purified ona silica gel column, eluting with 10% ethyl acetate in hexane, to obtain1.27 g (47%) of the aldehyde as a clear oil. ¹H NMR (300 MHz, CDCl₃): δ2.80 (m, 2H); 2.98 (m, 2H); 7.27 (m, 5H); 9.81 (2, 1H).

[0265] 1,2-Diphenyl-3-pentanol

[0266] A solution of 2-(bromoethyl)benzene (1.73 g; 9.33 mmol) indiethylether (10 ml) was added to a stirred slurry of magnesium turnings(250 mg; 10.18 mmol) in 5 ml of ether. The reaction was initiated with aheat gun, and after the addition was complete the mixture was heated onan oil bath for 30 min. 3-Phenyl-1-propanal (1.25 g; 9.33 mmol) wasadded in 10 ml of ether, and reflux was continued for 1 hour. Thereaction was cooled and quenched with saturated ammonium chloride,extracted into 2× ethyl acetate, and the combined organic portions weredried and concentrated. Chromatographic purification on a silica gelcolumn (10% ethyl acetate in hexane) delivered 1.42 g(63%) of thediphenyl alcohol. ¹H NMR (300 MHz, CDCl₃): δ 1.84 (m, 4H); 2.61-2.76 (m,4H); 3.65 (m, 1H); 7.19-7.29 (m, 10H).

[0267] 1,2-Diphenyl-3-bromopentane

[0268] To a solution of 1,5-diphenyl-3-pentanol (1.20 g (5 m=ol) andcarbon tetrabromide (1.67 g; 5 mmol) in methylene chloride (20 ml) wasadded triphenylphosphine (1.31 g; 5 mmol) portionwise, at 0° C. Afterstirring at room temperature for 18 hours, the mixture was concentrated,triturated with ether, and the solids removed by filtration. Thefiltrate was passed through a plug of silica gel, eluting withhexane:methylene chloride, 10:1, to give 1.35 g (90%) of the bromide asan oil which was used without further purification. ¹H NMR (300 MHz,CDCl₃): δ 2.11-2.18 (m, 4H); 2.73 (m, 2H); 2.86 (m, 2H); 3.95 (m, 1H);7.16-7.30 (m, 10H).

[0269] 1,2-Diphenyl-3-pentylmercaptan

[0270] Using the procedure described in Example 10 for the conversion ofbromides to thiols, 1,5-diphenyl-3-bromopentane was converted to1,5-diphenyl-3-pentylmercaptan in 35% overall yield. ¹H NMR (300 MHz,CDCl₃): δ 1.79 (m, 2H); 1.98 (m, 2H); 2.71 (m, 3H); 2.80 (m, 2H);7.16-7.28 (m, 10H).

[0271] 1,5-Diphenyl-3-pentylmercaptyl N-(tert-butyloxycarbonyl)pyrrolidine-2-carboxylate

[0272] A mixture of N-(tert-butyloxycarbonyl)-(S)-pipecolic acid (2.11g; 9.29 mmol), 1,5-diphenyl-3-pentylmercaptan (2.58 g; 10.22 mmol),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.96 g;10.22 mmol) and 4-dimethylaminopyridine (catalytic) in dry methylenechloride (50 ml) was stirred overnight, the reaction mixture was dilutedwith methylene chloride (50 ml) and water (100 ml), and the layers wereseparated. The organic phase was washed with water (3×100 ml), driedover magnesium sulfate, and concentrated to provide 870 mg (20%) of theproduct as a thick oil, which was used without further purification.

[0273] 1,5-Diphenyl-3-pentylmercaptyl pyrrolidine-2-carboxylate

[0274] A solution of 1,5-diphenyl-3-pentylmercaptylN-(tert-butyloxycarbonyl)pyrrolidine-2-carboxylate (850 mg; 1.8 mmol) inmethylene chloride (10 ml) and trifluoroacetic acid (1 ml) was stirredat room temperature for three hours. Saturated potassium carbonate wasadded until the pH was basic, and the reaction mixture was extractedwith methylene chloride. The combined organic extracts were dried andconcentrated to yield 480 mg (72%) of the free amine as a thick oil,which was used without further purification.

[0275] 1,5-Diphenyl-3-pentylmercaptyl N-(para-toluenesulfonyl)pipecolate

[0276] 1,5-Diphenyl-3-pentylmercaptylN-(para-toluenesulfonyl)pipecolate(18) was prepared from1,5-diphenyl-3-pentylmercaptyl pyrrolidine-2-carboxylate andpara-toluenesulfonyl chloride as described for Example 12, in 65% yield.¹H NMR (CDCl₃, 300 MHz): δ 0.80 (m, 4H); 1.23-1.97 (m, 5H); 2.15 (d,1H); 2.61-2.69 (m, 4H); 3.23 (m, 1H); 3.44 (dm, 1H); 4.27 (s, 2H); 4.53(d, 1H,

=4.5); 5.06 (m, 1H); 7.16-7.34 (m, 15H).

Example 14 Synthesis of 3-phenyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate (1)

[0277] Methyl (2S)-1-(1,2-dioxo-2-methoxyethyl)-2-pyrrolidinecarboxylate

[0278] A solution of L-proline methyl ester hydrochloride (3.08 g; 18.60mmol) in dry methylene chloride was cooled to 0° C. and treated withtriethylamine (3.92 g; 38.74 mmol; 2.1 eq). After stirring the formedslurry under a nitrogen atmosphere for 15 min, a solution of methyloxalyl chloride (3.20 g; 26.12 mmol) in methylene chloride (45 ml) wasadded dropwise. The resulting mixture was stirred at 0° C. for 1.5 hour.After filtering to remove solids, the organic phase was washed withwater, dried over MgSO₄ and concentrated. The crude residue was purifiedon a silica gel column, eluting with 50% ethyl acetate in hexane, toobtain 3.52 g (88%) of the product as a reddish oil. Mixture ofcis-trans amide rotamers; data for trans rotamer given. ¹H NMR (CDCl₃):d 1.93 (dm, 2H); 2.17 (m, 2H); 3.62 (m, 2H); 3.71 (s, 3H); 3.79, 3.84(s, 3H total); 4.86 (dd, 1H,

=8.4, 3.3).

[0279] Methyl(2S)-1-(1,2-dioxo-3,3-dimethylpentyl)-2-pyrrolidinecarboxylate

[0280] A solution of methyl(2S)-1-(1,2-dioxo-2-methoxyethyl)-2-pyrrolidinecarboxylate (2.35 g;10.90 mmol) in 30 ml of tetrahydrofuran (THF) was cooled to −78° C. andtreated with 14.2 ml of a 1.0 M solution of 1,1-dimethylpropylmagnesiumchloride in THF. After stirring the resulting homogeneous mixture at−78° C. for three hours, the mixture was poured into saturated ammoniumchloride (100 ml) and extracted into ethyl acetate. The organic phasewas washed with water, dried, and concentrated, and the crude materialobtained upon removal of the solvent was purified on a silica gelcolumn, eluting with 25% ethyl acetate in hexane, to obtain 2.10 g (75%)of the oxamate as a colorless oil. ¹H NMR (CDCl₃): d 0.88 (t, 3H); 1.22,1.26 (s, 3H each); 1.75 (dm, 2H); 1.87-2.10 (m, 3H); 2.23 (m, 1H); 3.54(m, 2H); 3.76 (s, 3H); 4.52 (dm, 1H,

=8.4, 3.4).

[0281] Synthesis of(2S)-1-(1,2-dioxo-3,3-dimethylpentyl)-2-pyrrolidinecarboxylic acid

[0282] A mixture of methyl(2S)-1-(1,2-dioxo-3,3-dimethylpentyl)-2-pyrrolidinecarboxylate (2.10 g;8.23 mmol), 1 N LiOH (15 ml), and methanol (50 ml) was stirred at 0° C.for 30 minutes and at room temperature overnight. The mixture wasacidified to pH 1 with 1 N HCl, diluted with water, and extracted into100 ml of methylene chloride. The organic extract was washed with brineand concentrated to deliver 1.73 g (87%) of snow-white solid which didnot require further purification. ¹H NMR (CDCl₃): d 0.87 (t, 3H); 1.22,1.25 (s, 3H each); 1.77 (dm, 2H); 2.02 (m, 2H); 2.17 (m, 1H); 2.25 (m,1H); 3.53 (dd, 2H,

=10.4, 7.3); 4.55 (dd, 1H,

=8.6, 4.1).

[0283] 3-Phenyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate (1)

[0284] A mixture of(2S)-1-(1,2-dioxo-3,3-dimethylpentyl)-2-pyrrolidine-carboxylic acid (600mg; 2.49 mmol), 3-phenyl-1-propanol (508 mg; 3.73 mmol),dicyclohexylcarbodiimide (822 mg; 3.98 mmol), camphorsulfonic acid (190mg; 0.8 mmol) and 4-dimethylaminopyridine (100 mg; 0.8 mmol) inmethylene chloride (20 ml) was stirred overnight under a nitrogenatmosphere. The reaction mixture was filtered through Celite to removesolids and concentrated in vacuo, and the crude material was purified ona flash column (25% ethyl acetate in hexane) to obtain 720 mg (80%) ofthe compound of Example 14 as a colorless oil. ¹H NMR (CDCl₃): d 0.84(t, 3H); 1.19 (s, 3H); 1.23 (s, 3H); 1.70 (dm, 2H); 1.98 (m, 5H); 2.22(m, 1H); 2.64 (m, 2H); 3.47 (m, 2H); 4.14 (m, 2H); 4.51 (d, 1H); 7.16(m, 3H); 7.26 (m, 2H)

Example 15

[0285] The method of Example 14 was utilized to prepare the followingillustrative compounds:

[0286] Compound 2: 3-phenyl-1-prop-2-(E)-enyl(2S)-1-3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate, 80%. ¹HNMR (360 MHZ, CDCl₃): d 0.86 (t, 3H); 1.21 (s, 3H); 1.25 (s, 3H);1.54-2.10 (m, 5H); 2.10-2.37 (m, 1H); 3.52-3.55 (m, 2H); 4.56 (dd, 1H,

=3.8, 8.9); 4.78-4.83 (m, 2H); 6.27 (m, 1H); 6.67 (dd, 1H,

=15.9); 7.13-7.50 (m, 5H).

[0287] Compound 3: 3-(3,4,5-trimethoxyphenyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate, 61%. ¹HNMR (CDCl₃): d 0.84 (t, 3H); 1.15 (s, 3H); 1.24 (s, 3H); 1.71 (dm, 2H);1.98 (m, 5H); 2.24 (m, 1H); 2.63 (m, 2H); 3.51 (t, 2H); 3.79 (s, 3H);3.83 (s, 3H); 4.14 (m, 2H); 4.52 (m, 1H); 6.36 (s, 2H).

[0288] Compound 4: 3-(3,4,5-trimethoxyphenyl)-1-prop-2-(E)-enyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidine carboxylate, 66%. ¹HNMR (CDCl₃): d 0.85 (t, 3H); 1.22 (s, 3H); 1.25 (s, 3H); 1.50-2.11 (m,5H); 2.11-2.40 (m, 1H); 3.55 (m, 2H); 3.85 (s, 3H); 3.88 (s, 6H); 4.56(dd, 1H); 4.81 (m, 2H); 6.22 (m, 1H); 6.58 (d, 1H,

=16); 6.63 (s, 2H).

[0289] Compound 5: 3-(4,5-methylenedioxyphenyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidine-carboxylate, 82%. ¹HNMR (360 MHZ, CDCl₃): d 0.86 (t, 3H); 1.22 (s, 3H); 1.25 (s, 3H)1.60-2.10 (m, 5H); 3.36-3.79 (m, 2H); 4.53 (dd, 1H,

=3.8, 8.6); 4.61-4.89 (m, 2H); 5.96 (s, 2H); 6.10 (m, 1H); 6.57 (dd, 1H,

=6.2, 15.8); 6.75 (d, 1H,

=8.0); 6.83 (dd, 1H,

=1.3, 8.0); 6.93 (s, 1H).

[0290] Compound 6: 3-(4,5-methylenedioxyphenyl)-1-prop-2-(E)-enyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate, 82%. ¹HNMR (360 MHZ, CDCl₃): d 0.86 (t, 3H); 1.22 (s, 3H); 1.25 (s, 3H);1.60-2.10 (m, 5H); 2.10-2.39 (m, 1H); 3.36-3.79 (m, 2H); 4.53 (dd, 1H,

=3.8, 8.6); 4.61-4.89 (m, 2H); 5.96 (s, 2H); 6.10 (m, 1H); 6.57 (dd, 1H,

=6.2, 15.8); 6.75 (d, 1H,

=8.0); 6.83 (dd, 1H,

=1.3, 8.0); 6.93 (s, 1H).

[0291] Compound 8: 3-cyclohexyl-1-prop-2-(E)-enyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate, 92%. ¹HNMR (360 MHZ, CDCl₃): d 0.86 (t, 3H); 1.13-1.40 (m +2 singlets, 9Htotal); 1.50-1.87 (m, 8H); 1.87-2.44 (m, 6H); 3.34-3.82 (m, 2H);4.40-4.76 (m, 3H); 5.35-5.60 (m, 1H); 5.60-5.82 (dd, 1H,

=6.5, 16).

[0292] Compound 9: (1R)-1,3-Diphenyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate, 90%. ¹HNMR (360 MHZ, CDCl₃) d 0.85 (t, 3H); 1.20 (s, 3H); 1.23 (s, 3H);1.49-2.39 (m, 7H); 2.46-2.86 (m, 2H); 3.25-3.80 (m, 2H); 4.42-4.82 (m,1H); 5.82 (td, 1H,

=1.8, 6.7); 7.05-7.21 (m, 3H); 7.21-7.46 (m, 7H).

[0293] Compound 10: 3-phenyl-1-propyl(2S)-1-(1,2-dioxo-2-[2-furanyl])ethyl-2-pyrrolidinecarboxylate, 99%. ¹HNMR (300 MHZ, CDCl₃): d 1.66-2.41 (m, 6H); 2.72 (t, 2H,

=7.5); 3.75 (m, 2H); 4.21 (m, 2H); 4.61 (m, 1H); 6.58 (m, 1H); 7.16-7.29(m, 5H); 7.73 (m, 2H).

[0294] Compound 11: 3-phenyl-1-propyl(2S)-1-(1,2-dioxo-2-[2-thienyl])ethyl-2-pyrrolidinecarboxylate, 81%. ¹HNMR (300 MHZ, CDCl₃): d 1.88-2.41 (m, 6H) 2.72 (dm, 2H); 3.72 (m, 2H);4.05 (m, 1H); 4.22 (m, 1H); 4.64 (m, 1H); 7.13-7.29 (m, 6H); 7.75 (dm,1H); 8.05 (m, 1H).

[0295] Compound 13: 3-phenyl-1-propyl(2S)-1-(1,2-dioxo-2-phenyl)ethyl-2-pyrrolidinecarboxylate, 99%. ¹H NMR(300 MHZ, CDCl₃): d 1.97-2.32 (m, 6H); 2.74 (t, 2H,

=7.5); 3.57 (m, 2H); 4.24 (m, 2H); 4.67 (m, 1H); 6.95-7.28 (m, 5H);7.51-7.64 (m, 3H); 8.03-8.09 (m, 2H).

[0296] Compound 14: 3-(2,5-dimethoxyphenyl)-1-propyl(2S)-i-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate, 99%. ¹HNMR (300 MHZ, CDCl₃): d 0.87 (t, 3H); 1.22 (s, 3H); 1.26 (s, 3H); 1.69(m, 2H); 1.96 (m, 5H); 2.24 (m, 1H); 2.68 (m, 2H); 3.55 (m, 2H); 3.75(s, 3H); 3.77 (s, 3H); 4.17 (m, 2H); 4.53 (d, 1H); 6.72 (m, 3H).

[0297] Compound 15: 3-(2,5-dimethoxyphenyl)-1-prop-2-(E)-enyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidine-carboxylate, 99%. ¹HNMR (300 MHZ, CDCl₃): d 0.87 (t, 3H); 1.22 (s, 3H); 1.26 (s, 3H) 1.67(m, 2H); 1.78 (m, 1H); 2.07 (m, 2H); 2.26 (m, 1H); 3.52 (m, 2H); 3.78(s, 3H); 3.80 (s, 3H); 4.54 (m, 1H); 4.81 (m, 2H); 6.29 (dt, 1H,

=15.9); 6.98 (s, 1H).

[0298] Compound 16: 2-(3,4,5-trimethoxyphenyl)-1-ethyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate, 97%. ¹HNMR (300 MHZ, CDCl₃): d 0.84 (t, 3H); 1.15 (s, 3H); 1.24 (s, 3H); 1.71(dm, 2H); 1.98 (m, 5H); 2.24 (m, 1H); 2.63 (m, 2H); 3.51 (t, 2H); 3.79(s, 3H); 3.83 (s, 3H); 4.14 (m, 2H); 4.52 (m, 1H); 6.36 (s, 2H).

[0299] Compound 17: 3-(3-Pyridyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate, 80%. ¹HNMR (CDCl₃, 300 MHZ): d 0.85 (t, 3H); 1.23, 1.26 (s, 3H each); 1.63-1.89(m, 2H); 1.90-2.30 (m, 4H); 2.30-2.50 (m, 1H); 2.72 (t, 2H); 3.53 (m,2H); 4.19 (m, 2H); 4.53 (m, 1H); 7.22 (m, 1H); 7.53 (dd, 1H); 8.45.

[0300] Compound 18: 3-(2-Pyridyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate, 88%. ¹HNMR (CDCl₃, 300 MHZ): d 0.84 (t, 3H); 1.22, 1.27 (s, 3H each); 1.68-2.32(m, 8H); 2.88 (t, 2H,

=7.5); 3.52 (m, 2H); 4.20 (m, 2H); 4.51 (m, 1H); 7.09-7.19 (m, 2H); 7.59(m, 1H); 8.53 (d, 1H,

=4.9).

[0301] Compound 19: 3-(4-Pyridyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate, 91%. ¹HNMR (CDCl₃, 300 MHZ): d 6.92-6.80 (m, 4H); 6.28 (m, 1H); 5.25 (d, 1H,

=5.7); 4.12 (m, 1H); 4.08 (s, 3H); 3.79 (s, 3H); 3.30 (m, 2H); 2.33 (m,1H); 1.85-1.22 (m, 7H); 1.25 (s, 3H); 1.23 (s, 3H); 0.89 (t, 3H,

=7.5).

[0302] Compound 20: 3-phenyl-1-propyl(2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate, 91%. ¹HNMR (CDCl₃, 300 MHZ): d 1.09-1.33 (m, 5H); 1.62-2.33 (m, 12H); 2.69 (t,2H,

=7.5); 3.15 (dm, 1H); 3.68 (m, 2H); 4.16 (m, 2H); 4.53, 4.84 (d, 1Htotal); 7.19 (m, 3H); 7.29 (m, 2H).

[0303] Compound 21: 3-phenyl-1-propyl(2S)-1-(2-tert-butyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate, 92%. ¹HNMR (CDCl₃, 300 MHZ): d 1.29 (s, 9H); 1.94-2.03 (m, 5H); 2.21 (m, 1H);2.69 (m, 2H); 3.50-3.52 (m, 2H); 4.16 (m, 2H); 4.53 (m, 1H); 7.19 (m,3H); 7.30 (m, 2H).

[0304] Compound 22: 3-phenyl-1-propyl(2S)-1-(2-cyclohexyl-ethyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate,97%. ¹H NMR (CDCl₃, 300 MHZ): d 0.88 (m, 2H); 1.16 (m, 4H); 1.43-1.51(m, 2H); 1.67 (m, 5H); 1.94-2.01 (m, 6H); 2.66-2.87 (m, 4H); 3.62-3.77(m, 2H); 4.15 (m, 2H); 4.86 (m, 1H); 7.17-7.32 (m, 5H).

[0305] Compound 23: 3-(3-pyridyl)-1-propyl(2S)-1-(2-cyclohexylethyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate, 70%.¹H NMR (CDCl₃, 300 MHZ): d 0.87 (m, 2H); 1.16 (m, 4H); 1.49 (m, 2H);1.68 (m, 4H); 1.95-2.32 (m, 7H); 2.71 (m, 2H); 2.85 (m, 2H); 3.63-3.78(m, 2H); 4.19 (m, 2H); 5.30 (m, 1H); 7.23 (m, 1H); 7.53 (m, 1H); 8.46(m, 2H).

[0306] Compound 24: 3-(3-pyridyl)-1-propyl(2S)-1-(2-tert-butyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate, 83%. ¹HNMR (CDCl₃, 300 MHZ): d 1.29 (s, 9H); 1.95-2.04 (m, 5H); 2.31 (m, 1H);2.72 (t, 2H,

=7.5); 3.52 (m, 2H); 4.18 (m, 2H); 4.52 (m, 1H); 7.19-7.25 (m, 1H); 7.53(m, 1H); 8.46 (m, 2H).

[0307] Compound 25: 3,3-diphenyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate, 99%. ¹HNMR (CDCl₃, 300 MHZ): d 0.85 (t, 3H); 1.21, 1.26 (s, 3H each); 1.68-2.04(m, 5H); 2.31 (m, 1H) 2.40 (m, 2H); 3.51 (m, 2H); 4.08 (m, 3H); 4.52 (m,1H); 7.18-7.31 (m, 10H).

[0308] Compound 26: 3-(3-pyridyl)-1-propyl(2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate, 88%. ¹HNMR (CDCl₃, 300 MHZ): d 1.24-1.28 (m, 5H); 1.88-2.35 (m, 11H); 2.72 (t,2H,

=7.5); 3.00-3.33 (dm, 1H); 3.69 (m, 2H); 4.19 (m, 2H); 4.55 (m, 1H);7.20-7.24 (m, 1H); 7.53 (m, 1H); 8.47 (m, 2H).

[0309] Compound 27: 3-(3-Pyridyl)-1-propyl (2S)-N-([2-thienyl]glyoxyl)pyrrolidinecarboxylate, 49%. ¹H NMR (CDCl₃, 300 MHZ): d1.81-2.39 (m, 6H); 2.72 (dm, 2H); 3.73 (m, 2H); 4.21 (m, 2H); 4.95 (m,1H); 7.19 (m, 2H); 7.61 (m, 1H); 7.80 (d, 1H); 8.04 (d, 1H); 8.46 (m,2H).

[0310] Compound 28: 3,3-Diphenyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxobutyl)-2-pyrrolidinecarboxylate, 99%. ¹HNMR (CDCl, 300 MHZ): d 1.27 (s, 9H); 1.96 (m, 2H); 2.44 (m, 4H); 3.49(m, 1H); 3.64 (m, 1H); 4.08 (m, 4H); 4.53 (dd, 1H); 7.24 (m, 10H).

[0311] Compound 29: 3,3-Diphenyl-1-propyl (2S)-1-cyclohexylglyoxyl-2-pyrrolidinecarboxylate, 91%. ¹H NMR (CDCl₃, 300 MHZ): d 1.32(m, 6H); 1.54-2.41 (m, 10H); 3.20 (dm, 1H); 3.69 (m, 2H); 4.12 (m, 4H);4.52 (d, 1H); 7.28 (m, 10H).

[0312] Compound 30: 3,3-Diphenyl-1-propyl (2S)-1-(2-thienyl)glyoxyl-2-pyrrolidinecarboxylate, 75%. ¹H NMR (CDCl₃, 300 MHZ): d 2.04(m, 3H); 2.26 (m, 2H); 2.48 (m, 1H); 3.70 (m, 2H); 3.82-4.18 (m, 3Htotal); 4.64 (m, 1H); 7.25 (m, 11H); 7.76 (dd, 1H); 8.03 (m, 1H).

Example 16

[0313] General procedure for the synthesis of acrylic esters,exemplified for methyl (3,3,5-trimethoxy)trans-cinnamate.

[0314] A solution of 3,4,5-trimethoxybenzaldehyde (5.0 g; 25.48 mmol)and methyl (triphenylphosphoranylidene)acetate (10.0 g; 29.91 mmol) intetrahydrofuran (250 ml) was refluxed overnight. After cooling, thereaction mixture was diluted with 200 ml of ethyl acetate and washedwith 2×200 ml of water, dried, and concentrated in vacuo. The cruderesidue was chromatographed on a silica gel column, eluting with 25%ethyl acetate in hexane, to obtain 5.63 g (88%) of the cinnamate as awhite crystalline solid. ¹H NMR (300 MHz; CDCl₃): d 3.78 (s, 3H); 3.85(s, 6H); 6.32 (d, 1H,

=16); 6.72 (s, 2H); 7.59 (d, H,

=16).

Example 17

[0315] General procedure for the synthesis of saturated alcohols fromacrylic esters, exemplified for (3,4,5-trimethoxy) phenylpropanol.

[0316] A solution of methyl (3,3,5-trimethoxy)-trans-cinnamate (1.81 g;7.17 mmol) in tetrahydrofuran (30 ml) was added in a dropwise manner toa solution of lithium aluminum hydride (14 mmol) in THF (35 ml), withstirring and under an argon atmosphere. After the addition was complete,the mixture was heated to 75° C. for 4 hours. After cooling, it wasquenched by the careful addition of 15 ml of 2 N NaOH followed by 50 mlof water. The resulting mixture was filtered through Celite to removesolids, and the filter cake was washed with ethyl acetate. The combinedorganic fractions were washed with water, dried, concentrated in vacuo,and purified on a silica gel column, eluting with ethyl acetate toobtain 0.86 g (53%) of the alcohol as a clear oil. ¹H NMR (300 MHz;CDCl₃): d 1.23 (br, 1H); 1.87 (m, 2H); 2.61 (t, 2H,

=7.1); 3.66 (t, 2H); 3.80 (s, 3H); 3.83 (s, 6H); 6.40 (s, 2H).

Example 18

[0317] General procedure for the synthesis of trans-allylic alcoholsfrom acrylic esters, exemplified for(3,4,5-trimethoxy)phenylprop-2-(E)-enol.

[0318] A solution of methyl (3,3,5-trimethoxy)-trans-cinnamate (1.35 g;5.35 mmol) in toluene (25 ml) was cooled to −10° C. and treated with asolution of diisobutylaluminum hydride in toluene (11.25 ml of a 1.0 Msolution; 11.25 mmol). The reaction mixture was stirred for 3 hours at0° C. and then quenched with 3 ml of methanol followed by 1 N HCl untilthe pH was 1. The reaction mixture was extracted into ethyl acetate andthe organic phase was washed with water, dried and concentrated.Purification on a silica gel column eluting with 25% ethyl acetate inhexane furnished 0.96 g (80%) of a thick oil. ¹H NMR (360 MHz; CDCl₃): d3.85 (s, 3H); 3.87 (s, 6H); 4.32 (d, 2H,

=5.6); 6.29 (dt, 1H,

=15.8, 5.7), 6.54 (d, 1H,

=15.8); 6.61 (s, 2H).

Example 19 In vivo Hair Generation Tests with C57 Black 6 Mice

[0319] Experiment A: C57 black 6 mice were used to demonstrate the hairrevitalizing properties of a pyrrolidine derivative, GPI 1046. Referringnow to FIGS. 1 and 2 of the drawings, C57 black 6 mice, approximately 7weeks old, had an area of about 2 inches by 2 inches on theirhindquarters shaved to remove all existing hair. Care was taken not tonick or cause abrasion to the underlaying dermal layers. The animalswere in anagen growth phase, as indicated by the pinkish color of theskin. Referring now to FIGS. 2, 3 and 4, four animals per group weretreated by topical administration with 20% propylene glycol vehicle(FIG. 2), 10 μM GPI 1046 (FIG. 3) or 30 μM GPI 1046 (FIG. 4) dissolvedin the vehicle. The animals were treated with vehicle or GPI 1046 every48 hours (3 applications total over the course of 5 days) and the hairgrowth was allowed to proceed for 6 weeks. Hair growth was quantitatedby the percent of shaved area covered by new hair growth during thistime period.

[0320]FIG. 2 shows that animals treated with vehicle exhibited only asmall amount of hair growth in patches or tufts, with less than 3% ofthe shaved area covered with new growth. In contrast, FIG. 3 shows thatanimals treated with 10 μM GPI 1046 exhibited dramatic hair growth,covering greater than 90% of the shaved area in all animals. Further,FIG. 4 shows that mice treated with 30 μM GPI 1046 exhibited essentiallycomplete hair regrowth and their shaved areas were indistinguishablefrom unshaven C57 black 6 mice.

[0321] Experiment B: C57 Black 6 mice were used to demonstrate the hairrevitalizing properties of various compounds of the present inventionand other related low molecular weight, small molecule compounds. C57Black 6 mice, 55 to 75 days old, had an area of about 2 inches by 2inches on their hindquarters shaved to remove all existing hair. Carewas taken not to nick or cause abrasion to the underlying dermal layers.The animals were in anagen growth phase when shaved. Five animals pergroup were treated by topical administration with a vehicle, FK506, apyrrolidine derivative of the present invention (GPI 1046), or anotherlow molecular weight, small molecule compound (GPI 1605, GPI 1312, GPI1572, GPI 1389, GPI 1511, or GPI 1234) to the shaved area. The animalswere treated three times per week, and hair growth was evaluated 14 daysafter initiation of treatment. Hair growth was quantitated by thepercent of shaved area covered by new hair growth, as scored by ablinded observer, on a scale of 0 (no growth) to 5 (complete hairregrowth in shaved area).

[0322]FIG. 5 shows that after 14 days, the animals treated with vehicleexhibited the beginning of hair growth in small tufts. By contrast, mostof the animals treated with the low molecular weight, small moleculepyrrolidine derivatives of the present invention and other relatedcompounds exhibited dramatic hair growth.

Example 20

[0323] A lotion comprising the following composition may be prepared.(%) 95% Ethanol 80.0 a pyrrolidine derivative 10.0 α-Tocopherol acetate0.01 Ethylene oxide (40 mole) adducts of hardened 0.5 castor oilpurified water 9.0 perfume and dye q.s.

[0324] Into 95% ethanol are added a pyrrolidine derivative, α-tocopherolacetate, ethylene oxide (40 mole) adducts of hardened castor oil,perfume and a dye. The resulting mixture is stirred and dissolved, andpurified water is added to the mixture to obtain a transparent liquidlotion.

[0325] 5 ml of the lotion may be applied once or twice per day to a sitehaving marked baldness or alopecia.

Example 21

[0326] A lotion comprising the following composition shown may beprepared. (%) 95% Ethanol 80.0 a pyrrolidine derivative 0.005 Hinokitol0.01 Ethylene oxide (40 mole) adducts of hardened 0.5 castor oilPurified water 19.0 Perfume and dye q.s.

[0327] Into 95% ethanol are added a pyrrolidine derivative, hinokitol,ethylene oxide (40 mole) adducts of hardened castor oil, perfume, and adye. The resulting mixture is stirred, and purified water is added tothe mixture to obtain a transparent liquid lotion.

[0328] The lotion may be applied by spraying once to 4 times per day toa site having marked baldness or alopecia.

Example 22

[0329] An emulsion may be prepared from A phase and B phase having thefollowing compositions. (%) (A phase) Whale wax 0.5 Cetanol 2.0Petrolatum 5.0 Squalane 10.0 Polyoxyethylene (10 mole) monostearate 2.0Sorbitan monooleate 1.0 a pyrrolidine derivative 0.01 (B phase)Glycerine 10.0 Purified water 69.0 Perfume, dye, and preservative q.s.

[0330] The A phase and the B phase are respectively heated and meltedand maintained at 80° c. Both phases are then mixed and cooled understirring to normal temperature to obtain an emulsion.

[0331] The emulsion may be applied by spraying once to four times perday to a site having marked baldness or alopecia.

Example 23

[0332] A cream may be prepared from A phase and B phase having thefollowing compositions. (%) (A Phase) Fluid paraffin 5.0 Cetostearylalcohol 5.5 Petrolatum 5.5 Glycerine monostearate 33.0 Polyoxyethylene(20 mole) 2-octyldoclecyl 3.0 ether Propylparaben 0.3 (B Phase) apyrrolidine derivative 0.8 Glycerine 7.0 Dipropylene glycol 20.0Polyethylene glycol 4000 5.0 Sodium Hexametaphosphate 0.005 Purifiedwater 44.895

[0333] The A phase is heated and melted, and maintained at 70° C. The Bphase is added into the A phase and the mixture is stirred to obtain anemulsion. The emulsion is then cooled to obtain a cream.

[0334] The cream may be applied once to 4 times per day to a site havingmarked baldness or alopecia.

Example 24

[0335] A liquid comprising the following composition may be prepared.(%) Polyoxyethylene butyl ether 20.0 Ethanol 50.0 a pyrrolidinederivative 0.001 Propylene glycol 5.0 Polyoxyethylene hardened castoroil 0.4 derivative (ethylene oxide 80 mole adducts) Perfume q.s.Purified water q.s.

[0336] Into ethanol are added polyoxypropylene butyl ether, propyleneglycol, polyoxyethylene hardened castor oil, a pyrrolidine derivative,and perfume. The resulting mixture is stirred, and purified water isadded to the mixture to obtain a liquid.

[0337] The liquid may be applied once to 4 times per day to a sitehaving marked baldness or alopecia.

Example 25

[0338] A shampoo comprising the following composition may be prepared.(%) Sodium laurylsulfate 5.0 Triethanolamine laurylsulfate 5.0 Betainelauryldimethylaminoacetate 6.0 Ethylene glycol distearate 2.0Polyethylene glycol 5.0 a pyrrolidine derivative 5.0 Ethanol 2.0 Perfume0.3 Purified water 69.7

[0339] Into 69.7 of purified water are added 5.0 g of sodiumlaurylsulfate, 5.0 g of triethanolamine laurylsulfate, 6.0 g of betainelauryldimethylaminoacetate. Then a mixture obtained by adding 5.0 g of apyrrolidine derivative, 5.0 g of polyethylene glycol, and 2.0 g ofethylene glycol distearate to 2.0 g of ethanol, followed by stirring,and 0.3 g of perfume are successively added. The resulting mixture isheated and subsequently cooled to obtain a shampoo.

[0340] The shampoo may be used on the scalp once or twice per day.

Example 26

[0341] A patient is suffering from alopecia senilis. A pyrrolidinederivative or a pharmaceutical composition comprising the same may beadministered to the patient. Increased hair growth is expected to occurfollowing treatment.

Example 27

[0342] A patient is suffering from male pattern alopecia. A pyrrolidinederivative or a pharmaceutical composition comprising the same may beadministered to the patient. Increased hair growth is expected to occurfollowing treatment.

Example 28

[0343] A patient is suffering from alopecia areata. A pyrrolidinederivative or a pharmaceutical composition comprising the same may beadministered to the patient. Increased hair growth is expected to occurfollowing treatment.

Example 29

[0344] A patient is suffering from hair loss caused by skin lesions. Apyrrolidine derivative or a pharmaceutical composition comprising thesame may be administered to the patient. Increased hair growth isexpected to occur following treatment.

Example 30

[0345] A patient is suffering from hair loss caused by tumors. Apyrrolidine derivative or a pharmaceutical composition comprising thesame may be administered to the patient. Increased hair growth isexpected to occur following treatment.

Example 31

[0346] A patient is suffering from hair loss caused by a systematicdisorder, such as a nutritional disorder or an internal secretiondisorder. A pyrrolidine derivative or a pharmaceutical compositioncomprising the same may be administered to the patient. Increased hairgrowth is expected to occur following treatment.

Example 32

[0347] A patient is suffering from hair loss caused by chemotherapy. Apyrrolidine derivative or a pharmaceutical composition comprising thesame may be administered to the patient. Increased hair growth isexpected to occur following treatment.

Example 33

[0348] A patient is suffering from hair loss caused by radiation. Apyrrolidine derivative or a pharmaceutical composition comprising thesame may be administered to the patient. Increased hair growth isexpected to occur following treatment.

[0349] The invention being thus described, it will be obvious that thesame may be varied in many ways. Such variations are not to be regardedas a departure from the spirit and scope of the invention and all suchmodifications are intended to be included within the scope of thefollowing claims.

We claim:
 1. A pharmaceutical composition which comprises: (i) aneffective amount of a non-immunosuppressive five-membered heterocycliccompound having a single nitrogen heteroatom, which has an N-linkedketone, diketo, thioketo, or 1-(2-(3-oxo) propene) substituent, andwhich is additionally substituted with an ester or amide substituentattached to the heterocyclic ring, provided that said ester or amidesubstituent is not an N-oxide of an ester or amide, for treatingalopecia or promoting hair growth in an animal in need thereof; (ii) asecond hair revitalizing agent; and (iii) a pharmaceutically acceptablecarrier.
 2. The pharmaceutical composition of claim 1 , wherein thecompound has an affinity for an FKBP-type immunophilin.
 3. Thepharmaceutical composition of claim 2 , wherein the FKBP-typeimmunophilin is FKBP-12.
 4. The pharmaceutical composition of claim 1 ,wherein the compound is of formula I

or a pharmaceutically acceptable salt, ester, or solvate thereof,wherein: R₁ is C₁-C₉ straight or branched chain alkyl, C₂-C₉ straight orbranched chain alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl or Ar₁, wherein said R₁ is unsubstituted or substituted with one or moresubstituents independently selected from the group consisting of C₁-C₆alkyl, C₂-C₆ alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, hydroxy, andAr₂; Ar₁ and Ar₂ are independently selected from the group consisting of1-naphthyl, 2-naphthyl, 2-indolyl, 3-indolyl, 2-furyl, 3-furyl,2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and phenyl, wherein said Ar₁ is unsubstituted or substituted with one or moresubstituent(s) independently selected from the group consisting ofhydrogen, halo, hydroxy, nitro, trifluoromethyl, C₁-C₆ straight orbranched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C₁-C₄alkoxy, C₂-C₄ alkenyloxy, phenoxy, benzyloxy, and amino; X is O, S, CH₂,or two hydrogen atoms; Y is O or NR₂; R₂ is hydrogen or C₁-C₆ alkyl; Zis C₁-C₆ straight or branched chain alkyl, or C₂-C₆ straight or branchedchain alkenyl,  wherein said Z is substituted with one or moresubstituent(s) independently selected from the group consisting of Ar₁,C₃-C₈ cycloalkyl, C₁-C₆ straight or branched chain alkyl substitutedwith C₃-C₈ cycloalkyl, and C₂-C₆ straight or branched chain alkenylsubstituted with C₃-C₈ cycloalkyl, or Z is the fragment

wherein: R₃ is C₁-C₉ straight or branched chain alkyl which isunsubstituted or substituted with C₃-C₈ cycloalkyl or Ar₁; X₂ is O orNR₅; R₅ is selected from the group consisting of hydrogen, C₁-C₆straight or branched chain alkyl, and C₂-C₆ straight or branched chainalkenyl; and R₄ is selected from the group consisting of phenyl, benzyl,C₁-C₅ straight or branched chain alkyl, C₂-C₅ straight or branched chainalkenyl, C₁-C₅ straight or branched chain alkyl substituted with phenyl,and C₂-C₅ straight or branched chain alkenyl substituted with phenyl. 5.The pharmaceutical composition of claim 4 , wherein Z and R₁ arelipophilic.
 6. The pharmaceutical composition of claim 4 , wherein thecompound is selected from the group consisting of: 3-phenyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;3-phenyl-1-prop-2-(E)-enyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;3-(3,4,5-trimethoxyphenyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;3-(3,4,5-trimethoxyphenyl)-1-prop-2-(E)-enyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;3-(4,5-dichlorophenyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;3-(4,5-dichlorophenyl)-1-prop-2-(E)-enyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;3-(4,5-methylenedioxyphenyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;3-(4,5-methylenedioxyphenyl)-1-prop-2-(E)-enyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;3-cyclohexyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;3-cyclohexyl-1-prop-2-(E)-enyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;(1R)-1,3-diphenyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;(1R)-1,3-diphenyl-1-prop-2-(E)-enyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;(1R)-1-cyclohexyl-3-phenyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;(1R)-1-cyclohexyl-3-phenyl-1-prop-2-(E)-enyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;(1R)-1-(4,5-dichlorophenyl)-3-phenyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;3-phenyl-1-propyl(2S)-1-(1,2-dioxo-2-cyclohexyl)ethyl-2-pyrrolidinecarboxylate;3-phenyl-1-propyl(2S)-1-(1,2-dioxo-4-cyclohexyl)butyl-2-pyrrolidinecarboxylate;3-phenyl-1-propyl(2S)-1-(1,2-dioxo-2-[2-furanyl])ethyl-2-pyrrolidinecarboxylate;3-phenyl-1-propyl(2S)-1-(1,2-dioxo-2-[2-thienyl])ethyl-2-pyrrolidinecarboxylate;3-phenyl-1-propyl(2S)-1-(1,2-dioxo-2-[2-thiazolyl])ethyl-2-pyrrolidinecarboxylate;3-phenyl-1-propyl(2S)-1-(1,2-dioxo-2-phenyl)ethyl-2-pyrrolidinecarboxylate;1,7-diphenyl-4-heptyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;3-phenyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxo-4-hydroxybutyl)-2-pyrrolidinecarboxylate;3-phenyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxamide;1-[1-(3,3-dimethyl-1,2-dioxopentyl)-L-proline]-L-phenylalanine ethylester; 1-[1-(3,3-dimethyl-1,2-dioxopentyl)-L-proline]-L-leucine ethylester; 1-[1-(3,3-dimethyl-1,2-dioxopentyl)-L-proline]-L-phenylglycineethyl ester;1-[1-(3,3-dimethyl-1,2-dioxopentyl)-L-proline]-L-phenylalanine phenylester; 1-[1-(3,3-dimethyl-1,2-dioxopentyl)-L-proline]-L-phenylalaninebenzyl ester; and1-[1-(3,3-dimethyl-1,2-dioxopentyl)-L-proline]-L-isoleucine ethyl ester;or a pharmaceutically acceptable salt, ester, or solvate thereof.
 7. Thepharmaceutical composition of claim 1 , wherein the compound is offormula II

or a pharmaceutically acceptable salt, ester, or solvate thereof,wherein: R₁ is C₁-C₉ straight or branched chain alkyl, C₂-C₉ straight orbranched chain alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl or Ar₁, wherein said R₁ is unsubstituted or substituted with one or moresubstituents independently selected from the group consisting of C₁-C₆alkyl, C₂-C₆ alkenyl, C₃-C₈ cycloalkyl, C₅-C₇ cycloalkenyl, hydroxy, andAr₂; Ar₁ and Ar₂ are independently selected from the group consisting of1-naphthyl, 2-naphthyl, 2-indolyl, 3-indolyl, 2-furyl, 3-furyl,2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl and phenyl, wherein said Ar₁ is unsubstituted or substituted with one or moresubstituent(s) independently selected from the group consisting ofhydrogen, halo, hydroxy, nitro, trifluoromethyl, C₁-C₆ straight orbranched chain alkyl, C₂-C₆ straight or branched chain alkenyl, C₁-C₄alkoxy, C₂-C₄ alkenyloxy, phenoxy, benzyloxy, and amino; Z is C₁-C₆straight or branched chain alkyl, or C₂-C₆ straight or branched chainalkenyl,  wherein said Z is substituted with one or more substituent(s)independently selected from the group consisting of Ar₁, C₃-C₈cycloalkyl, C₁-C₆ straight or branched chain alkyl substituted withC₃-C₈ cycloalkyl, and C₂-C₆ straight or branched chain alkenylsubstituted with C₃-C₈ cycloalkyl, or Z is the fragment

wherein: R₃ is C₁-C₉ straight or branched chain alkyl which isunsubstituted or substituted with C₃-C₈ cycloalkyl or Ar₁; X₂ is O orNR₅; R₅ is selected from the group consisting of hydrogen, C₁-C₆straight or branched chain alkyl, and C₂-C₆ straight or branched chainalkenyl; and R₄ is selected from the group consisting of phenyl, benzyl,C₁-C₅ straight or branched chain alkyl, C₂-C₅ straight or branched chainalkenyl, C₁-C₅ straight or branched chain alkyl substituted with phenyl,and C₂-C₅ straight or branched chain alkenyl substituted with phenyl. 8.The pharmaceutical composition of claim 7 , wherein R₁ is selected fromthe group consisting of C₁-C₉ straight or branched chain alkyl,2-cyclohexyl, 4-cyclohexyl, 2-furanyl, 2-thienyl, 2-thiazolyl, and4-hydroxybutyl.
 9. The pharmaceutical composition of claim 7 , wherein Zand R₁ are lipophilic.
 10. The pharmaceutical composition of claim 1 ,wherein the compound is of formula III

or a pharmaceutically acceptable salt, ester, or solvate or hydratethereof, wherein: Z′ is the fragment

wherein: R₃ is C₁-C₉ straight or branched chain alkyl or unsubstitutedAr₁,  wherein said alkyl is unsubstituted or substituted with C₃-C₈cycloalkyl or Ar₁; X₂ is O or NR₅; R₅ is selected from the groupconsisting of hydrogen, C₁-C₆ straight or branched chain alkyl, andC₂-C₆ straight or branched chain alkenyl; R₄ is selected from the groupconsisting of phenyl, benzyl, C₁-C₅ straight or branched chain alkyl,C₂-C₅ straight or branched chain alkenyl, C₁-C₅ straight or branchedchain alkyl substituted with phenyl, and C₂-C₅ straight or branchedchain alkenyl substituted with phenyl; and Ar₁ is independently selectedfrom the group consisting of 1-naphthyl, 2-naphthyl, 2-indolyl,3-indolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl,4-pyridyl and phenyl,  wherein said Ar₁ is unsubstituted or substitutedwith one or more substituent(s) independently selected from the groupconsisting of hydrogen, halo, hydroxy, nitro, trifluoromethyl, C₁-C₆straight or branched chain alkyl, C₂-C₆ straight or branched chainalkenyl, C₁-C₄ alkoxy, C₂-C₄ alkenyloxy, phenoxy, benzyloxy, and amino.11. The pharmaceutical composition of claim 10 , wherein Z′ islipophilic.
 12. The pharmaceutical composition of claim 1 , wherein thecompound is of formula IV

or a pharmaceutically acceptable salt, ester, or solvate thereof,wherein: R₁ is C₁-C₆ straight or branched chain alkyl, C₂-C₆ straight orbranched chain alkenyl, C₃-C₆ cycloalkyl or Ar₁,  wherein said alkyl oralkenyl is unsubstituted or substituted with C₃-C₆ cycloalkyl or Ar₂;Ar₁ and Ar₂ are independently selected from the group consisting of2-furyl, 2-thienyl, and phenyl; X is selected from the group consistingof oxygen and sulfur; Y is oxygen; Z is C₁-C₆ straight or branched chainalkyl or C₂-C₆ straight or branched chain alkenyl,  wherein said Z issubstituted with one or more substituent(s) independently selected fromthe group consisting of 2-furyl, 2-thienyl, C₃-C₆ cycloalkyl, pyridyl,and phenyl, each having one or more substituent(s) independentlyselected from the group consisting of hydrogen and C₁-C₄ alkoxy.
 13. Thepharmaceutical composition of claim 12 , wherein Z and R₁ arelipophilic.
 14. The pharmaceutical composition of claim 12 , wherein thecompound is selected from the group consisting of:3-(2,5-dimethoxyphenyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;3-(2,5-dimethoxyphenyl)-1-prop-2-(E)-enyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;2-(3,4,5-trimethoxyphenyl)-1-ethyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;3-(3-pyridyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;3-(2-pyridyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;3-(4-pyridyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;3-phenyl-1-propyl(2S)-1-(2-tert-butyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate;3-phenyl-1-propyl(2S)-1-(2-cyclohexylethyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate;3-(3-pyridyl)-1-propyl(2S)-1-(2-cyclohexylethyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate;3-(3-pyridyl)-1-propyl(2S)-1-(2-tert-butyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate;3,3-diphenyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;3-(3-pyridyl)-1-propyl(2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate;3-(3-pyridyl)-1-propyl (2S)-N-([2-thienyl]glyoxyl)pyrrolidinecarboxylate; 3,3-diphenyl-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxobutyl)-2-pyrrolidinecarboxylate;3,3-diphenyl-1-propyl (2S)-1-cyclohexylglyoxyl-2-pyrrolidinecarboxylate;and 3,3-diphenyl-1-propyl (2S)-1-(2-thienyl)glyoxyl-2-pyrrolidinecarboxylate; or a pharmaceutically acceptable salt,ester, or solvate thereof.
 15. The pharmaceutical composition of claim14 , wherein the compound is selected from the group consisting of:3-(3-pyridyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate;3-(2-pyridyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate; and3-(3-pyridyl)-1-propyl(2S)-1-(2-cyclohexyl-1,2-dioxoethyl)-2-pyrrolidinecarboxylate; or apharmaceutically acceptable salt, ester, or solvate thereof.
 16. Thepharmaceutical composition of claim 15 , wherein the compound is3-(3-pyridyl)-1-propyl(2S)-1-(3,3-dimethyl-1,2-dioxopentyl)-2-pyrrolidinecarboxylate, or apharmaceutically acceptable salt, ester, or solvate or hydrate thereof.17. The pharmaceutical composition of claim 1 , wherein the compound isan N-glyoxyl prolyl ester.
 18. A pharmaceutical composition whichcomprises: (i) an effective amount of a compound of formula V

or a pharmaceutically acceptable salt, ester, or solvate thereof,wherein: V is CH or N; A and B, taken together with V and the carbonatom to which they are respectively attached, form a 5-7 memberedsaturated or unsaturated heterocyclic ring containing one or moreheteroatom(s) selected from the group consisting of O, S, SO, SO₂, N,NH, and NR; R is C₁-C₉ straight or branched chain alkyl, C₂-C₉ straightor branched chain alkenyl, C₃-C₉ cycloalkyl, C₅-C₇ cycloalkenyl, or Ar₁, wherein said R is either unsubstituted of substituted with one or moresubstituent(s) independently selected from the group consisting of halo,haloalkyl, carbonyl, carboxy, hydroxy, nitro, trifluoromethyl, C₁-C₆straight or branched chain alkyl, C₂-C₆ straight or branched chainalkenyl, C₁-C₄ alkoxy, C₂-C₄ alkenyloxy, phenoxy, benzyloxy, thioalkyl,alkylthio, sulfhydryl, amino, alkylamino, aminoalkyl, aminocarboxyl, andAr₂; R₁ is C₁-C₉ straight or branched chain alkyl, C₂-C₉ straight orbranched chain alkenyl, C₃-C₇ cycloalkyl, C₅-C₇ cycloalkenyl, or Ar₁, wherein said R₁ is unsubstituted or substituted with one or moresubstituents independently selected from the group consisting of C₁-C₆alkyl, C₂-C₆ alkenyl, C₃-C₈ cycloalkyl, C₁-C₇ cycloalkenyl, hydroxy, andAr₂; Ar₁ and Ar₂ are independently an alicyclic or aromatic, mono-, bi-or tricyclic, carbo- or heterocyclic ring,  wherein the ring is eitherunsubstituted or substituted with one or more substituent(s),  whereinthe individual ring size is 5-8 members,  wherein said heterocyclic ringcontains 1-6 heteroatom(s) independently selected from the groupconsisting of O, N, and S; X is O, S, CH₂, or two hydrogen atoms; Y is Oor NR₂; R₂ is hydrogen or C₁-C₆ alkyl; Z is C₁-C₆ straight or branchedchain alkyl or C₂-C₆ straight or branched chain alkenyl,  wherein said Zis substituted with one or more substituent(s) independently selectedfrom the group consisting of Ar₁, C₃-C₈ cycloalkyl, C₁-C₆ straight orbranched chain alkyl substituted with C₃-C₈ cycloalkyl, and C₂-C₆straight or branched chain alkenyl, or Z is the fragment

wherein: R₃ is C₁-C₉ straight or branched chain alkyl which isunsubstituted or substituted with C₃-C₈ cycloalkyl or Ar₁; X₂ is O orNR₅; R₅ is selected from the group consisting of hydrogen, C₁-C₆straight or branched chain alkyl, and C₂-C₆ straight or branched chainalkenyl; and R₄ is selected from the group consisting of phenyl, benzyl,C₁-C₅ straight or branched chain alkyl, C₂-C₅ straight or branched chainalkenyl, C₁-C₅ straight or branched chain alkyl substituted with phenyl,and C₂-C₅ straight or branched chain alkenyl substituted with phenyl;(ii) a second hair revitalizing agent; and (iii) a pharmaceuticallyacceptable carrier.